Physiol. Rev.
84: 649-698, 2004; doi:10.1152/physrev.00031.2003
0031-9333/04
$15.00
Role of
Extracellular Matrix
in Adaptation of Tendon and Skeletal Muscle to Mechanical
Loading
MICHAEL KJÆR
Sports Medicine Research Unit, Department of
Rheumatology, Copenhagen University Hospital at Bispebjerg, Copenhagen, Denmark
 649 -- Physiological Reviews_files/rarrow.gif) |
ABSTRACT |
Kjær,
Michael. Role of
Extracellular Matrix
in Adaptation of
Tendon and Skeletal Muscle to Mechanical Loading. Physiol Rev
84: 649–698, 2004; 10.1152/physrev.00031.2003.—The extracellular matrix
(ECM), and especially the connective tissue with its collagen, links
tissues of the body together and plays an
important role in the force transmission and tissue
structure maintenance especially in tendons, ligaments, bone, and
muscle. The ECM turnover is influenced by physical activity, and
both collagen synthesis and degrading metalloprotease enzymes
increase with mechanical loading. Both transcription and
posttranslational modifications, as well as local and systemic
release of growth factors, are enhanced
following exercise. For tendons, metabolic activity, circulatory
responses, and collagen turnover are demonstrated to be more
pronounced in humans than hitherto thought. Conversely, inactivity
markedly decreases collagen turnover in both tendon and muscle.
Chronic loading in the form of
physical training leads both to increased collagen turnover as well
as, dependent on the type of
collagen in question, some degree of net
collagen synthesis. These changes will modify the mechanical
properties and the viscoelastic characteristics of the
tissue, decrease its stress, and likely make it more load resistant.
Cross-linking in connective tissue involves an intimate, enzymatical
interplay between collagen synthesis and ECM proteoglycan components
during growth and maturation and influences the collagen-derived
functional properties of the
tissue. With aging, glycation contributes to additional cross-linking
which modifies tissue stiffness. Physiological signaling pathways
from mechanical loading to changes in ECM most likely involve
feedback signaling that results in rapid alterations in the
mechanical properties of the ECM. In developing skeletal
muscle, an important interplay between muscle cells and the ECM is
present, and some evidence from adult human muscle suggests common
signaling pathways to stimulate contractile and ECM components.
Unaccostumed overloading responses suggest an important role
of ECM in the adaptation of
myofibrillar structures in adult muscle.
Development of overuse injury in tendons involve
morphological and biochemical changes including altered collagen
typing and fibril size, hypervascularization zones, accumulation
of nociceptive substances, and impaired
collagen degradation activity. Counteracting these phenomena
requires adjusted loading rather than absence of
loading in the form of
immobilization. Full understanding of
these physiological processes will provide the physiological basis
for understanding of
tissue overloading and injury seen in both tendons and muscle with
repetitive work and leisure time physical activity.
|
I.
INTRODUCTION |
Extracellular matrix
(ECM) placed in tendon tissue as well as periand intramuscularly
ensures a functional link between the skeletal muscle cell and the
bone. Despite this important role, it is surprising how little is
known about ECM compared with the insight into the biology
of both skeletal muscle and bone. The
role of
contractile filaments in skeletal muscle is well appreciated in
relation to force development (286,
319,
415,
445),
as is the role of the
adjacent tendon tissue functioning as a passive structure in
transforming this developed force from the muscle to the bone with
mechanical loading (459,
525,
532),
thereby allowing for joint movement of the
body (16,
69,
70,
116,
282,
283,
459,
550).
Signals from mechanical loading will initiate a cascade leading from
gene expression, transcription, translation, and posttranslational
process modification to the integration of
events to provide protein synthesis in the ECM (699).
These mechanisms are however only partly understood. Furthermore, to
what extent the connective tissue and the muscular tissue share
signaling pathways that ensure an optimal coordinated transformation
of loading activity (both tissue stretching
and contractile activity) into structural and functional
adaptation of both muscle fibers and extramuscular tissue is
not very well described (163,
417,
654).
The ECM consists of a variety of
substances, of which collagen fibrils and
proteoglycans are truly ubiquitous (153).
In addition to the proteoglycans (PG), the hydrophilic ECM includes
(164,
339,
581)
a variety of other proteins such as noncollagen
glycoproteins (582,
583).
It is known that the force transmission of the
muscle-tendon complex is dependent on the structural integrity
between individual muscle fibers and the ECM (48)
as well as the fibrillar arrangement of the
tendon and its allowance for absorption and loading of energy (15,
16).
Furthermore, it is well described that the tensile strength
of the matrix
is based on intra- and intermolecular cross-links, the orientation,
density, and length of both the collagen fibrils and fibers
(57,
447,
496,
497,
630–632,
640).
However, the signals triggering the connective tissue cells in
response to mechanical loading, and the subsequent expression and
synthesis of specific extracellular matrix
proteins, as well as its coupling to the mechanical function
of the tissue are only partly described
(51–53,
173,
181).
This review focuses on the physiological role
of the ECM, especially collagen, for
the tendon-muscle interaction and the adaptation to mechanical
loading. Somewhat in contrast to the classical view of the
ECM tissue being relatively static and inert, evidence is evolving
that tendons and intracellular connective tissue are more dynamic
structures that adapt to the variety of
functional demands that the musculoskeletal system is subjected to,
and that this tissue adapts both in a structural and functional
way to mechanical loading (53,
173,
386,
630).
Recent development of
refined in vivo techniques have underlined that connective tissue
of skeletal muscle and tendon is a lively
structure with a dynamic protein turnover and that it possesses the
capacity to adapt greatly to changes in the external environment
such as mechanical loading or inactivity and disuse.
|
II.
CONVERSION OF MECHANICAL LOADING INTO TISSUE ADAPTATION
OF TENDON AND EXTRACELLULAR MATRIX OF SKELETAL MUSCLE: THE GENERAL CONCEPT
|
Mechanotransduction
is an important mechanism by which mechanical stress acts upon a cell
and initiates intracellular signaling, promotes cell growth and
survival (222,
530,
544,
556,
625),
governs morphology and architecture in several cell types (125,
197,
589,
639,
697),
and influences metabolic responses (287).
Various cells respond differently to mechanical challenges, and
the molecular basis for mechanotransduction, especially related to
the cell membrane, has been a topic for a recent review and will not
be dealt with further here (254).
It is however clear that with regard to ECM of
tendon and skeletal muscle, any mechanical stimulus is suspected to
initiate an adaptation that would make the tissue more damage
resistant to ensure an optimal force transmission with muscular
contractions.
The ECM is a conglomerate of
substances in which biochemical and biophysical properties allow for
the construction of a flexible network that integrates
information from loading and converts it into mechanical capacities
(152,
494,
690).
It serves as a scaffold for adhesion of
cells mediated by integrins, dystroglycan, and proteoglycans at the
cell surface and of tyrosine kinase receptors (98,
290).
The interaction between the ECM and the adhesion molecules leads to
activation of intracellular signaling pathways and
cytoskeletal rearrangement (52,
82,
114).
In combination with this, the PGs with their glycosaminoglycan side
chains are able to bind and present growth factors to their
relevant receptors, and furthermore, the ECM can release growth
factors upon relevant mechanical stimulation. The complete
signaling pathways responsible for mechanotransduction responses are
yet to be described, but several candidates have been suggested
from investigations on a variety of
fibroblasts in dermis, vasculature, and cardiac muscle (166,
396,
667).
Integrin molecules are major structural components of
adhesion complexes at the cell membrane linking the ECM to the
cytoskeleton (108,
128,
541).
In this way integrins establish a mechanical continuum along which
forces can be transmitted from the outside to the inside
of the cell, and vice versa (238,
290,
291,
667,
668).
It is believed that integrins are the sensors of
tensile strain at the cell surface (290).
Ingber et al. (291)
have suggested that integrins together with the cytoskeleton form a
mechanically sensitive organelle. At the myotendinous junction, lack
of integrin expression will lead to
structural damage during muscle contraction (442).
Integrins are important structural components of the
adhesion complexes at the cell membrane, and they play a crucial
role in linking the ECM to the
cytoskeleton (227,
412,
418,
419,
579).
Thereby they provide a bridge through which forces can be
transmitted between inside and outside of the
cells in a two-way street principle. Further evidence for this is
provided by the fact that integrins can convert mechanical signals to
adaptive responses in the cell (115,
591).
In addition to integrins, also the dystrophin-glycoprotein complex
plays an important role in mechanotransduction of
muscle and tendon tissue (107,
130,
288).
The  649 -- Physiological Reviews_files/beta.gif)
-subunit cytoplasmic domain of
integrin is interacting with the cytoskeleton, and the demonstration
of  649 -- Physiological Reviews_files/alpha.gif)
71-integrin linked to laminin in the ECM is
important for signal transduction (81,
309a,
309b),
and lack of the 2-laminin leads to muscle dystrophy. Interestingly,
overexpression of
71-integrin in dystrophin-deficient mice leads to
reduction in dystrophic symptoms, indicating that some substitution
effects exist between integrin and laminin (107).
Extracellular matrix ligands for integrins are known
to be collagens, fibronectin, tenascin, and laminin (412).
Several studies have demonstrated that the expression of
several other ECM components are controlled by the level
of mechanical loading. For example, collagen
XII and tenascin-C, which are present in both tendon and other
connective tissue structures like ligaments, have been shown to
increase their expression and synthesis when fibroblasts are
stretched in vitro and are suppressed in cells that are left in a
relaxed state (127,
129).
Although not yet confirmed, integrins are likely candidates for
sensing tensile stress at the cell surface (290,
683,
694,
698).
Thus some evidence indicates that integrin-associated proteins are
involved in the signaling adaptive cellular responses to mechanical
loading of the tissue, and it is likely that this
takes also place in tendon and skeletal muscle ECM-related
fibroblasts (531).
Several intracellular pathways for mechanotransduction signaling
have been suggested, including focal adhesion kinase (FAK),
paxillin, integrin-linked kinase (ILK-1), and mitogen-activated
protein kinase (MAPK) (127,
206,
207,
241,
451,
618).
MAPK is crucial for the conversion of
mechanical load to tissue adaptation inducing signaling from the
cytosol to the nucleus. It is well described that several cell types
and subsets of MAPKs such as extracellular signal-regulated kinase 1 and 2
(MAPK-erk1+2, p44), stress-activated protein kinases p38 (MAPK-p38),
c-jun NH2-terminal kinase (MAPK-jnk, p54), and
extracellular signal-regulated kinase 5
(MAPK-erk5) can be activated by mechanical stress, as well as by
lowered pH, growth factors, hormones, and reactive oxygen species (250,
414,
678,
693,
696).
In regard to mechanical loading, it has been shown in muscle that
MAPK can be activated both as a result of
active muscle contraction (36,
37,
559)
and after passive stretch (161,
439).
The activation of MAPK results not only in a
production of transcription factors, thus
mediating gene expression, but also in an activation of
the protein synthesis on the translational level through
eukaryotic initiation and elongation factors (229).
It has furthermore been suggested that the mode of
mechanical load is coupled to a certain type of
MAPK activation. In line with this, it has recently been shown in rat
skeletal muscle cells that concentric activation of
muscle associated with metabolic and ionic changes resulted in a
preferential increase in MAPK-erk1+2, whereas intense eccentric
tensile loading with barely any metabolic changes resulted in a
marked increase in MAPK-p38 (as well as in MAPK-erk 1+2) (693).
In another study that also used rat skeletal muscle, a strong
relationship was found between peak tension (whether active and/or
passive) and MAPK-jnk (439).
This falls in line with the demonstration of
MAPK-jnk activation and the induction of
immediate early genes by mechanical stress in smooth muscle cells (253).
Whether any marked increase in MAPK-p38 is found in skeletal muscle
is still debatable. Whereas one study could not find any increase in
MAPK-p38 in rat muscle during concentric, stretch, or eccentric
muscle activity (439),
another study found a marginal and late increase in MAPK-p38
(37,
241)
while a third study found MAPK-p38 activation in exercised human
skeletal muscle (674).
It has been shown that activation in skeletal muscle of
MAPK-p38 is fiber-type specific (243).
Somewhat in contrast to muscle, it seems very clear that in
connective tissue MAPK-p38 is mainly activated with mechanical
stretching of the tissue (127).
Findings on regulation of matrix metalloproteinase (MMP)
activation in fibroblasts point toward a differentiated interplay
between MAPKs, in which MAPK-p38 is important for induction
of MMP, while MAPK-erk1+2 mediates the
repression (534).
Although not conclusive, these findings are compatible with stress
pattern-dependent MAPK pathways in both the muscle cell and the
fibroblast and suggest an intimate interplay between the muscle cell
and intramuscular connective tissue in response to mechanical
loading. Evidently, such pathways do not in any way rule out other
mechanistic pathways (e.g., calcium-dependent pathways) to be
involved in mechanotransduction also (36).
Taken together, it is likely that separate modes of
tissue loading and thereby of
physical training will differentially stimulate the subtypes
of MAPK in both myocytes and fibroblasts.
Most likely, endurance like oxidative loading of
tissue stimulates MAPK-erk, whereas strength type of
exercise is more likely to use the MAPK-jnk pathway (693).
Furthermore, passive stretch both in muscle and connective tissue
preferentially gives rise to stimulation of
MAPK-p38 (89).
In human models, stretch does not cause any increased muscle protein
synthesis, and thus does not result in any hypertrophic effect on the
muscle (211).
The fact that the stretch of
muscle cells and of fibroblast shows parallel MAPK
activation suggests that adaptive processes in intramuscular
connective tissue interact closely with those of
skeletal muscle tissue when subjected to mechanical loading.
|
III.
TENDON AND SKELETAL MUSCLE EXTRACELLULAR MATRIX CONTENT: ORGANIZATION AND
PHYSIOLOGICAL FUNCTION |
A. Tendon
Components
Tendons consist of a systematic and densely packed
organization of
connective tissue dominated by collagen organized into fibrils,
fibers, fiber bundles, and fascicles, as well as by the presence
of other ECM proteins. The nature of the
individual components of the
tendon is equipped to withstand high tensile forces (224,
627,
632).
The division of tendons into fibrils ensures that
minor damage does not necessarily spread to the entire tendon,
and also provides a high total structural strength (Fig.
1). Tendon consists of
55–70% water, and a substantial part of
this is associated with proteoglycans in the ECM (187,
307,
546,
659,
660).
Of the tendon dry weight, 60–85% is collagen.
This collagen is predominantly type I ( 649 -- Physiological Reviews_files/sim.gif)
60%) arranged in tensile-resistant fibers, and composed
of two 1- and one 2-chains. These are products of
separate genes rather than a posttranslational modification
of a single molecule. Also, collagen types III
(reported between 0 and 10%), IV (2%) (12,
260),
V, and VI are present (72,
74,
307,
324,
652,
653).
In addition to this, a small amount of elastin fibers are present (2% of dry weight) (194,
195,
307).
Apart from a very small amount of
inorganic substance (<0.2%), the remaining substance consists
of different proteins (accounting for
4.5%) (660),
but very little information is present as to the relative
contribution of these (10b).
It has been shown that the inorganic substance is dominated by PGs,
especially small leucine-rich proteins of
which decorin (up to 1%) (164,
307,
660)
and cartilage oligomeric matrix
protein (COMP, up to 1%) (465,
601,
604)
are probably the most abundant. In addition, other small leucine-rich
PGs such as fibromodulin, biglycan (up to 0.5%), and lumican,
together with osteoadherin, tenascin-C, proline argininerich end
leucine-rich repeat protein, optican, keratocan, epiphycan, syndican,
perlecan, agrin, fibronectin, laminin, vercican, and aggrecan are
present in tendon tissue (300,
307,
537).
The PGs and water are thought to have a spacing and lubricating
role for the tendon, whereas the role
for several of the small and nonaggregating leucinerich PGs is
more unclear. The proteoglycans also seem to play an important
role in fibril fusion, as do fibrillin
molecules aligning along fibrils (50).
Tendons vary markedly in design, most likely coupled to their
function. In the quadriceps the tendon can be found to be short
and thick, whereas several of the
tendons to the fingers or toes are long and thin. Furthermore,
tendons may vary in thickness along its length and are often
surrounded by loose connective tissue lined with synovial cells, the
paratenon, to allow for large movements of the
tendon. The epitenon is the connective tissue sheet that immediately
surrounds the tendon, and it consists of
loose, fatty, areolar tissue that allows for the tendon together with
the tendon sheet, the peritendon, to glide against adjacent tissue
(574).
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FIG. 1. Structure
of tendon tissue. Sections
of tendon tissue. Top left: a
transverse section of a tendon stained with hematoxylin
and eosin. In the center of the section a fascicle with
fibroblasts is seen surrounded by loose connective tissue endotenon
(arrow). Top right: a confocal laser-scanning microscopy
image of a transverse tendon section. High
power view of a three-dimensional reconstruction
shows adjacent fibroblasts within a fascicle. It is notable that the
cells have sheetlike processes toward each other. Bottom left
and right: transverse and longitudinal section, respectively,
of a tendon stained with
immunnofluorescence labeling for the gap
junction protein, connexin43 (green, indicated by yellow arrows on
the longitudinal view, bottom right). Sections are
counterstained with propidium iodide (red) to indilsecate fibroblast
nuclei. This indicates the gap junction coupling between tendon
fibroblasts and supports the view of a communicative network
of tendon cells. [Modified from
Benjamin and co-workers (62,
447,
528)
and personal communication with M. Benjamin.]
| |
B. Tendon
Fibroblast Signaling
Tendons are dominated by fibroblasts. In addition, also other cell
types like endothelial cells and mast cells as well as axons are,
together with the ECM, also present in tendons. It has been
demonstrated that tendon fibroblasts lie in longitudinal rows and
have numerous sheet-like cell extensions that extend far into the ECM
(447)
(Fig.
1). Isolated tendon fibroblasts respond to mechanically induced
loading with expression of
several ECM components (53).
In the intact tendon, cells are linked to each other via gap
junctions as evidenced by immunolabeling for connexin32 and
connexin43 (447,
528).
Where the latter represents the meeting of
cell processes as well as where cell bodies meet, the former only
represents contact between cell bodies. In total, the architecture
of the fibroblasts of the
tendon and their interconnection provides a three-dimensional network
that surrounds the collagen fibrils and provides a basis for
cell-to-cell interaction. In vitro, tendon cells upregulate collagen
and gap junction production under mechanical cyclic loading, and
pharmacological inhibition of the
gap junction leads to loss of
this response (52,
662).
Gap junctions must under loading be able to withstand high loads and
have been shown to be coupled to the actin cytoskeleton (394,
395,
695).
In articular chondrocytes and compressed tendon regions, a
compression-sensitive organization of
intermediate filaments has been shown (179,
528,
529).
As well actin filaments and fibers have been shown in developing
intervertebral discs and in scar connective tissue (194).
However, the demonstration of
these has not been put into a functional perspective (331,
469).
It has been demonstrated that in knockout mice for the intermediate
filament vimentin, -smooth muscle actin organization is abnormal in dermal
fibroblasts and that their contractile ability is impaired (180).
Recently, it has been shown that tendons have actin-based cell-cell
interaction (515)
and that actin stress fibers run along the rows of
fibroblasts (529).
When mechanically loaded, junctional components n-cadherin and
vinculin rose together with tropomyosin, without any change in actin
levels. The rise in cadherin and vinculin suggests an increased
cell-cell adhesion or cell-matrix
adhesion. This suggests that mechanical load transforms fibers into
partly contractile components that may contribute to an active
mechanism in the recovery after stretch and that these structures
can maintain the integrity of the
longitudinal tendon rows and to monitor tensile load and contribute
in the mechanotransduction during exercise (529).
C.
Tendon Vasculature and Blood Flow Regulation
Compared with muscle, tendons have relatively limited vasculature,
and the area occupied by vessels represents 1–2% of the entire ECM (373,
374).
The vessels mainly emanate from the epitenon where longitudinal
vessels run into the endotenon (10c,
341,
373,
374).
Supplying arteries and arterioles may come from the perimysium at the
musculotendinous junction and vessels from the tendon bone junction
(113,
137,
574).
Long tendons are supplied by several vessels along their length (271,
341).
Due to the large excursion (up to 6 cm) that some tendons experience
during movement, the vessels to such tendons need to be long and
often winding in nature.
The ECM in relation to both muscle and tendon is extensively
filled with blood vessels (508,
509),
to provide the contracting muscle with oxygen and substrate for
energy production, and to ensure an efflux from musculature
of combustion products. It remains,
however, unsolved to what extent the blood flow to connective tissue
alters with mechanical loading of the
tissue. In the resting state, rabbit tendons have been shown to
have tendon flow of
around one-third of that in muscle, and it is known that
blood flow in both tendons and ligaments increase with exercise and
during healing in animals (46).
Both with the use of
radiolabeled xenon washout technique from peritendon tissue as well
as with application of near-infrared spectroscopy and
simultaneous infusion of contrast substance (95),
it has been possible to demonstrate in human models that blood
flow within and around tendon connective tissue increases up to
sevenfold during exercise, both in young, middle-aged, and elderly
individuals (93,
94,
377,
378,
381).
This increase is by far smaller that the 20-fold increase in adjacent
skeletal muscle blood flow under similar exercise conditions (93,
94).
However, compared with the metabolic activity of the
tendon during exercise, it might be adequate. Furthermore, it can be
shown that skeletal muscle blood flow during maximal exercise is
close to what is possible to achieve with postocclusion reactive
hyperemia, while the flow in tendon is still only 20% of
that during maximal exercise (93,
94).
This implies that tendon flow is not simply a function of
skeletal muscle blood flow and that its regulation represents a
separate regulatory system.
Vasodilatory agents have been measured simultaneously in skeletal
muscle and its adjacent tendon during mechanical loading in
vivo, and it has been found that adenosine concentrations rise
in an intensity-dependent fashion in muscle, whereas the changes
in tendon were less marked and unrelated to intensity (375).
Furthermore, bradykinin concentrations rose in parallel in the
two tissues during exercise, and already elicited its maximal
response at low exercise loads (375).
The changes in tissue bradykinin concentrations are in the range that
has been found to cause a vasodilatory effect on endothelium (554).
These findings indicate that these two substances are involved in
blood flow regulation in skeletal muscle and tendon with exercise and
that bradykinin is involved in the blood flow increase during
lower work loads both in tendon and muscle. Whether bradykinin
exerted its vasodilatory effect directly on the vasculature (109)
or more indirectly via release of
other substances as nitric oxide (NO) (490),
prostaglandins (58),
or endothelium-derived hyperpolarizing factor (EDHF) (279,
458)
is yet to be established.
Interestingly, it has been shown that prostaglandin concentrations
rise both in muscle (214,
317)
and in connective peritendinous tissue (385)
with exercise. Whereas inhibition of
prostaglandin synthesis by itself did not inhibit total flow during
exercise in skeletal muscle, but did so only if simultaneous
blockade also of NO
synthesis was performed (96),
the peritendinous and tendinous blood flow during exercise was
diminished by 40–50% compared with control exercise without blockade
(376).
This differentiated regulation of
blood flow regulation in skeletal muscle and tendon tissue,
respectively, can be hypothesized to imply also a differentiated
regulation of blood flow within the skeletal
muscle itself. This would be so if parts of
the vasculature in muscle is located in regions with abundance
of ECM, i.e., aponeurosis and
perimysial tissue. The finding of flow heterogeneity within skeletal
muscle as well as the demonstration of
nutritive and nonnutritive vessels in skeletal muscle (94,
95,
137)
are certainly supporting evidence for such an idea. It would also
explain a separate role during exercise for vessels that
were very responsive to vasodilation dependent on work load and thus
providing maximal supplementation of
substrate and oxygen to the muscle, and on the other hand
vasculature located in connective tissue, both within the muscle and
in relation to tendon tissue, where flow is coupled to
inflammatory activity in repair processes for the ECM. The latter
would also serve as a kind of
shunt with the potential of
partly limiting its vasodilation to share blood with the nutritive
vessels during exercise.
With regard to the ECM, the main question remains whether the
increase in flow is sufficient to meet the oxidative needs of the tendon and its cells during
exercise. Determination of
oxygen saturation and content of the
Achilles tendon region in humans has been performed using
near-infrared spectroscopy with the addition of a
dye dilution method (94–96).
When simultaneous recording of
tissue oxygenation and blood flow of
human tendon regions was performed both at rest and during muscular
contractions, it can be demonstrated that a tight correlation exists
between increasing blood flow and declining oxygen tissue
saturation (334)
(Fig.
2). This correlation could indicate a coupling and fits very well
with what is found in skeletal muscle during exercise (96).
This illustrates that during exercise the estimated oxygen uptake in
humans tendon regions rises severalfold compared with the resting
state and that even during intense mechanical loading of
tendons, there is no indication of any
tissue ischemia.
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FIG. 2. Blood flow
during rest and exercise in human tendon and muscle. The correlation
between spatially resolved near infrared spectroscopy (SRS) oxygen
saturation and blood flow either in leg gastrocnemius muscle or in
the Achilles tendon region. Regional tissue flow was determined with
use of indocyanine green dye infusion in
combination with SRS, and values during rest (2 ml·100 g–1·min–1 in tendon) and
during graded increasing plantar flexion exercise with the calf
muscle until exhaustion. The correlation was tested for significance
by the use of the Spearmann test. Note that even
during intense exercise the average tissue O2 saturation
did not decrease below 57% for skeletal muscle and 52% for tendon
tissue. [From Boushel and co-workers (93,
94)
and Kjær et al. (334)
with permission.]
| |
D.
ECM Components in Skeletal Muscle
Intramuscular connective tissue has multiple functions (301a,
407)
(Fig.
3). First it provides a basic mechanical support for vessels and
nerves. Second, the connective tissue ensures the passive elastic
response of muscle. Third, it is now clear that
force transmission from the muscle fibers not only is transformed to
tendon and subsequent bone via the myotendinous junctions but also
via lateral transmission between neighboring fibers and fascicles
within a muscle (228,
338,
415,
626).
It has been shown that tension developed in one muscle part can be
transmitted via shear links to other parts of the
muscle, and that even the cutting of an
aponeurosis in a pennate muscle still maintains much of the
force transmission (401).
The perimysium is especially capable of
transmitting tensile force (631).
Although studies have also demonstrated a potential of the
endomysium for force transmission, the orientation and curvilinearity
of the collagen fibers provide high
amounts of elasticity and thus not sufficient
stiffness to function optimally as a force transmitter.
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FIG. 3. Structure
of intramuscular connective tissue.
Skeletal muscle (bovine semitendinosus muscle) extracellular network shown by
scanning electron micrographs after removal of skeletal muscle protein. Top
left shows the epimysium (EP), and the bottom illustrates
the perimysium (P) as well as the endomysium (E). On the top
right, the endomysium surrounding one individual skeletal muscle
fiber is shown. [Modified from Nishimura et al. (483).]
| |
Intramuscular connective tissue accounts for 1–10% of the skeletal muscle and varies quite
substantially between muscles (208,
301,
391,
628)
(Fig.
3). Whereas the endomysium encloses each individual muscle fiber
with random arrangement of
collagen fibrils to allow for movement during contraction, the
multisheet-layered perimysium runs transversely to fibers and holds
groups of fibers in place, while the epimysium
is formed of two layers of
wavy collagen fibrils to form a sheetlike structure at the
surface of the tendon. It has been demonstrated in bovine
muscles that the endomysial content can vary between 0.5 and 1.2% of the muscle dry weight, whereas the
perimysium accounts for between 0.4 and 4.8% (520).
This relatively small variation in the endomysial compared with
perimysial connective tissue content between muscles could indicate
that at least some functional differences between muscle groups
related to connective tissue content are mainly defined by perimysial
characteristics. The intramuscular connective tissue is dominated by
collagen and ensures not only an organization into fasicles and
fibers, but contributes importantly to the force transmission (39).
Several collagen types have been identified in intramuscular
connective tissue (up to 7) (174,
410,
411),
and whereas type IV dominates the basement membrane adjacent to
the plasma membrane of the sarcolemma (12,
342),
the fibrillar collagen type I and III (and to some extent type V)
dominates the epi-, peri-, and endomysium (the reticular layer). By
far type I collagen dominates the intramuscular collagen content
(reported from 30% and up to 97% of
total collagen) (47,
48,
257,
407).
At the other end of the scale, collagen types II, VI,
IX, XI-XVI, and XVIII-XIX represent only very minor amounts (88a,
167,
252a,
410,
411,
440,
471,
486).
It is likely that the difference in relative content of
connective tissue in specific muscles is coupled to function and the
role of
connective tissue (247,
248).
Differences between muscles with regard to their relative content and
type of collagen is already present early in
development (483,
485),
and in cattle, the concentration of
hydroxyproline as well as of
collagen type I and III achieve their highest levels two-thirds
through gestation (411).
Interestingly, the highest collagen concentrations are achieved at
the time when myotubes undergo their first phase of
morphological and contractile differentiation (411).
Furthermore, small leucine-rich proteoglycans of
intramuscular connective tissue are expressed in parallel with
development of skeletal muscle (506).
Decorin and fibromodulin mRNA were markedly elevated for a few
days, and biglycan and lumican for 1 wk postnatally (485).
Interestingly, during this period the structure of the
intramuscular connective tissue changes markedly, thereby the
neonatal structure is less organized than that seen just 2–3 wk later
(672).
The increases in PG expression are paralleled by increases in
myostatin expression and transforming growth factor- (TGF-) and could suggest an interplay between the development
of skeletal muscle and intramuscular
connective tissue (485,
672).
E.
Functional Implications of ECM
in Tendon and Muscle
It is important to accept that both tendon and intramuscular
connective tissue interact closely with the contractile elements
of the skeletal muscle to transmit force (521,
562,
566,
567,
573,
610,
675,
691).
The dimensions of tendons will influence the ability
to stretch, and the ability of the
tendon and the intramuscular connective tissue to store and release
elastic energy during movement reduces the overall energy need
during walking or running (15,
71).
Some of the evidence for the functional
importance of ECM components stems from studies of
mutant knockout models. Given its important role
in basal membrane formation, it might be obvious that mice lacking
laminin will result in growth retardation and muscle dystrophy.
Furthermore, mutations of
integrins will also lead to muscle dystrophy and in collagen type VI
to myopathy (303,
442).
In mice lacking collagen type IX or XI, abnormal collagen fibrils
will be found especially in relation to joints (199,
397),
while in animals lacking type X collagen chondrodysplasia will
develop (666).
Furthermore, a defect in types IV, IX, XIII, and type XV collagen
will cause myopathy symptomatology (87,
88a,
185,
367).
Knockout models for collagen type I, especially when accompanied by
mechanical loading, have been difficult to study, in that these
animals develop severe osteogenesis imperfecta (126).
Finally, somewhat interestingly, in models for proteoglycan defects
in the form of a fibromodulin-null mouse, irregular collagen
fibrils in tendon structure was observed, whereas no changes were
detected in bone or cartilage (615).
Mice lacking biglycan and fibromodulin will experience ectopic tendon
ossification (27).
In line with this, in mice lacking COMP, no clear musculotendinous
abnormalities could be found, whereas in humans without COMP,
skeletal dysplasias are observed (267).
The limitation of these models is the concept
of redundance, a phenomenon that is likely to be
present also in the ECM, as it can be demonstrated for regulation
of circulation and release
of hormones in relation to exercise (333,
334).
An important role in linking together the fibrous elements
of the ECM whether in muscle or tendon
are the proteoglycans (111,
572, 581,
583,
584,
673).
Within muscle, it has been demonstrated that PGs in the perimysium
are rich in chondroitin and dermatan sulfate. In contrast, those PGs
that are present in the endomysium and the basal membrane are
dominated by heparan sulfates (484).
In addition, decorin has been demonstrated to be present in at
least bovine muscle closely associated with chondroitin sulfate (183,
480),
and this is dominant in muscles during the early embryonic and
postnatal state (644,
645),
whereas heparan sulfate is dominant in the late embryonic state.
Although several of the ECM substances in addition to
collagen have been located in tendon (and muscle), little information
on its functional role
has been provided. One of the leucine-rich small proteoglycans
that envelopes the collagen fibrils is decorin (583).
Knockout of decorin suggests the involvement of
decorin in the formation of
collagen fibrils and to some extent controls the diameter
of the fibril and prevents any lateral fusion
of collagen fibrils (111,
156).
Furthermore, inhibition of
decorin results in larger collagen fibrils and increased mechanical
properties in healing ligaments (478,
479).
The clear role of
decorin, or any coordinated effect of
either fibromodulin or lumican situated in the same region as
decorin, but having different binding sites (268,
616),
is not definitively clear (119,
196,
616).
More recently, it has been shown in chick embryonic tendon that small
leucine-rich PGs like decorin are bound to collagen even before
collagen fibril assembly, and this suggests a much earlier
involvement of decorin and other PGs than thought so far (245).
Even though PGs and glycosaminoglycans are important for tendon
function, it has been suggested that neither these nor the collagen
fibril size in itself can explain the biomechanical capacities
of tendon tissue, therefore suggesting
a more complex interplay involving factors and component
of tendon tissue yet to be described.
One of the large chondroitin sulfate PGs, aggrecan, is
largely upregulated upon compressive loading of the
tendon tissue, whereas decorin only responds to tensile loading (548,
549),
and is likely to be involved in the preference to synthesize type
II collagen in regions of
tendons that are subjected to compressive forces (61,
62,
528).
Compressed areas of tendon are found to have increased
amounts of larger weight PGs (200,
557).
This illustrates the differentiated response to tensile and
compressive loading, respectively, on collagen and ECM proteoglycans
(663,
664).
|
IV.
REGULATION OF COLLAGEN AND OTHER EXTRACELLULAR MATRIX PROTEIN SYNTHESIS: INFLUENCE
OF CHANGES IN MECHANICAL LOADING
|
A.
Steps of Collagen Synthesis: Methodological
Considerations
The major component of the ECM, collagen, is produced in
principal by fibroblasts either on the membrane-bound ribosomes
of the rough endoplasmic reticulum (ER)
or placed within the ECM, respectively. Collagen biosynthesis is
characterized by the presence of
an extensive number of
coand posttranslational modifications of the polypeptide chains, which
contribute to the quality and stability of the
collagen molecule (Fig.
4). Intracellularly, translation of
preprocollagen mRNA occurs in ribosomes and procollagen assembly in
the endoplasmatic reticulum (437,
443,
661).
C-propeptide domains of
polypeptide -chains fold, and trimerization initiates the triple helix
formation in fibrillar collagen types. These events depend on a
well-matched interaction of ER
enzymes like prolyl-4-hydroxylase (P-4-H),
galactosylhydroxy-lysyl-glucosyltransferase (GGT), lysyl hydroxylase,
prolyl-3-hydroxylase, hydroxylysylgalactosyltransferase as well as on
heat shock protein 47, glucose regulating protein 94, and protein
disulfide isomerase (201,
202,
368,
473,
539,
561,
568,
604).
Genetic information for procollagen chain formation is divided into
several exons in the DNA separated by relatively large intron areas
and thus demands extensive processing of RNA prior to that mature mRNA being
available for protein synthesis (661).
Procollagens are transferred from ER to the extracellular space through the Golgi
apparatus and contain NH2-terminal and COOH-terminal
extension peptides at the respective ends of
the collagen molecule (264).
The fact that procollagen is larger that the conventional transport
vesicles necessitates transport within the Golgi apparatus (88).
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FIG. 4. Collagen type
I synthesis and degradation. Schematic representation of pathways involved in collagen
synthesis. Potential growth factor candidates that function as
important regulators of gene avtivation are indicated.
TGF-b, transforming growth factor-; IGF/IGF-BP, insulin-like growth factor and its binding
proteins; IL, interleukin; FGF, fibroblast growth factor; PG,
prostaglandin; VEGF, vasoactive endothelial growth factor.
Mitogen-activated protein kinase (MAPK) plays an important
regulatory role for initiation of gene signaling, and matrix metalloproteinases (MMP) are
major regulators of collagen degradation in relation to
mechanical loading.
| |
After secretion into the extracellular space, the amino-propeptides
are cleaved by specific proteinases and the collagens self-assemble
into fibrils or other supramolecular structures (516)
(Fig.
3). The synthesis of
collagen fibrils occurs first as an intracellular step with
assembling and secretion of
procollagen, followed by an extracellular step converting the procollagen into
collagen and subsequent incorporation into stable cross-linked
collagen fibrils (Fig.
3). The synthesis of type I collagen is used here to
illustrate the fibrillar collagen formation, due to its dominance in
the connective tissue of tendon and muscle, but synthesis
of other collagen types shares many similarities
with that of collagen type I, but is described
further in this review. Following the transcription of
genes coding for the formation of
collagen type I, the pro--chains initially synthesized undergo marked
posttranslational reactions. First, hydroxylation converts residues
to 4-hydroxyproline or 3-hydroxyproline by three different
hydroxylases (473).
Interestingly, the hydroxylases only act on nonhelical substrates and
do not act on collagen or collagen-like peptides that are triple
helical. Newly synthesized collagen polypeptides are glycosylated,
and this process ends before the folding of collagen into a triple helix
structure. Finally, the intracellular processing completes with the
synthesis of both intrachain and interchain
disulfide bonds (170).
This last process is not started before the translation is completed
and probably not before the chains are released from ribosome. The
procollagen is then secreted from the cell, and it is well described
that the rate of
secretion depends on the intracellular processing of
the protein. If folding of the
pro--chains into the triple helical confirmation is prevented,
secretion of the protein is delayed. The three
polypeptide chains form a triple-helical structure. The -chains forming the structure are composed of
repeating amino acid sequences Gly-X-Y, where the glycine residue
enables the three -chains to coil around one another. Proline and 4-hydroxyproline
residues appear frequently at the X- and Y-positions, respectively,
and promote the formation of
intermolecular cross-links. The stability and quality of the
collagen molecule is largely based on the intra- and intermolecular
cross-links. The 4-hydroxyproline formation is catalyzed by P-4-H and
is a unique feature of collagen. Thus its assay is suitable
for evaluating collagen content. Levels of
P-4-H activity generally increase and decrease with the rates
of collagen biosynthesis, and assays of the
enzyme activity have been used for estimating changes in the rate
of collagen biosynthesis in various
experimental and physiological conditions (256–258,
318,
474,
569–571,
619,
620).
The exact location of the processing of
procollagen to collagen might however be more complex than that (533).
Procollagen N-proteinase (called ADAMTS-2) has recently been cloned
(142,
143),
and procollagen C-proteinase has been documented to be identical to
bone morphometric protein (BMP-1) (327,
398)
in which, at least in mouse embryonic tendon, all three protein
variants of BMP-1 are expressed (541,
580).
Recent experiments in embryonic chicken tendon using pulse-chase
followed by sequential extraction have revealed that both intra-
and extracellular pools of
active procollagen C-proteinase (BMP-1) are present in fibroblasts,
whereas the N-proteinase is located in close proximity or within the
plasma membrane (91,
111).
Conversion of extracellular procollagen to collagen was
prevented when procollagen C-proteinase was blocked, whereas on the
other hand, collagen fibrils were seen in post-Golgi vesicles
and tubules (111).
Therefore, despite demonstrated procollagen to collagen conversion
being completed extracellularly, some collagen
formation may be completed intracellularly and the sequence
of C- and N-proteinase in converting procollagen
into collagen appears to be more random than so far thought (111).
Fibril segments are prerequisites for fibril formation (496,
497)
and have been shown to increase in length from a few microns to 100 µm (76–78),
and gradually develop increasing diameter (203,
204).
It is likely that fibrils develop into different mass profiles, where some are regular linear ones,
some are very short and spindle-shaped, and some are intermediary
fusing fibers (245,
492).
The collagen molecules are arranged either unipolar or bipolar (245,
312,
313)
and fuse end to end (77,
78).
Most likely as a result of MMP
activity from the fibroblasts, this end-to-end fusion is followed by
increased decorin formation (77,
78)
and removal of collagen type XIV from fibril surfaces
(703).
The fibrillar structure and the tissue's resistance toward loading is
yet to be clarified (135,
231),
but it is known that the cross-link-deficient tendons are less
resistant to loading (680)
and that the elongation of the
tendon depends on molecular gliding within the collagen fibrils (215,
519).
Proteoglycans are important for fibrillogenesis (156,
164,
702),
and when decorin/fibronectrin binding is inhibited, tendon length
is increased (112).
Determination of pyridinoline (Pyr), which represents
important components of cross-links of
mature collagen fibers within the ECM, has shown that the content
of Pyr is especially high in tendon and
ligaments, and interestingly also that the Pyr-to-collagen ratio
appears to be high in tendon and ligament compared with, e.g., bone
(237).
This underlines the likely importance of
cross-links in these structures (339)
and stresses the complexity in studying structure-function
relationship with regard to connective tissue as tendon, ligaments,
and to some extent skeletal muscle (194).
B.
Determination of Collagen Turnover in Humans
To determine turnover rates for collagen, radiolabeled amino acids
have been introduced (387–389).
These allow for labeling of
substances such as proline, which are incorporated into the collagen.
If infused they will result in an increase in the specific activity
of a certain tissue removed from the
experimental species at a selected time point. The calculation
of turnover rates initially however was based on
first-order decay curves that rely on the prerequisite that all
collagen molecules are equally likely to be degraded. If, which has
been shown, the collagen pool is subdivided into a more fast and
a more slow exchanging pool, this method likely gave a pessimistic
picture of the capability to turnover collagen (387).
More recently, the use of
techniques "flooding" the precursor pool to reduce or eliminate
reutilization and using infusion over a relatively short time has
been performed successfully (44).
Microdialysis of both muscle and connective tissue has been
performed with the intention to mimic the function of a
capillary blood vessel by perfusing a thin dialysis tube with a
physiological fluid implanted into the tissue (384–386).
This allows for collection of
extracellular fluid both in animals and in
humans in vivo, both with the organism in a basal state as well
as during conditions where physiological perturbations are performed,
whether these are chemical or mechanical. The collection of dialysate allows for calculation
of interstitial concentration
of unbound substances that are able to cross the
membrane of the catheter, provided the technique
is supplemented by calibration methods that allow for quantitation
of this. Using microdialysis fibers
along the peritendon also provides the possibility to study during
exercise. For several metabolic parameters it has been shown that
determinations peritendinously reflect the changes that occur
intratendinously (379).
C.
Responses to Increased Loading: Acute and Chronic Exercise
Muscular and tendinous collagen and the connective tissue network
are known to respond to altered levels of
physical activity (347–350,
507,
612,
613,
623,
658,
682,
688,
706).
The specific activities and content of
collagen components are known to be greater in the antigravity soleus
muscle than in the dorsiflexor tibialis anterior, which is not
tonically active (349,
569).
Furthermore, ECM in skeletal muscle is known to respond to increased
loading caused by endurance training (348,
349,
619,
711),
acute exercise (474),
or experimental compensatory hypertrophy (676)
by increased collagen expression, synthesis, and collagen
accumulation in the muscle. Strenuous exercise, especially acute
weight-bearing exercise that contains eccentric components, is known
to cause muscle damage (33).
Upregulation of collagen synthesis may be a part
of the repair process but may also occur without
any evidence of
muscle damage (256).
Acceleration of collagen biosynthesis after exercise
may thus reflect both physiological adaptation and repair
of damage.
It has been found in mice that acute exercise increases activities
of enzymes of
collagen turnover 48 h after exercise. Enzymes responsible for
collagen synthesis were increased, and the most in muscles dominated
by red rather than white muscle fibers (474,
650,
651).
This fits with the demonstration of
higher content of
collagen, as measured by amount of
hydroxyproline, in red versus white muscle fiber dominated muscles,
and with a high recruitment of red
fiber muscles during the specific exercise protocol (349).
Interestingly, the changes in collagen enzyme activities were
accompanied by a rise in both hydroxyproline and collagen content
of the exercised muscle, which persisted
up to 3 wk after exercise (474,
650,
651).
Later studies have demonstrated that expression of
types I and III collagen was increased at the mRNA level within 1 day
(257,
345)
and that of type IV collagen as early as 6 h after acute
exercise (344).
Extracellular conversion of
procollagen to collagen requires at least two enzymes: a procollagen
aminoprotease that removes the aminopeptides and a procollagen
carboxyprotease that removes the carboxy propeptides. The cleavage
of the carboxypeptide allows for
indirect determination of collagen type I formation.
Development of assays for such markers of
type I collagen synthesis [the COOH-terminal propeptide of
type I collagen (PICP)] and degradation [the COOH-terminal
telopeptide region of type I collagen (ICTP)] has made it
possible to study the effect of exercise on collagen type I turnover
(99).
When determined in circulating blood, these markers have been shown
to be relatively insensitive to a single bout of
exercise, whereas prolonged exercise or weeks of
training were shown to result in increased type I collagen turnover
and net formation (383).
However, as bone is the main overall contributor of
procollagen markers for collagen type I turnover in the blood, and as
serum levels of
PICP and ICTP do not allow for detection of the
location of the specific type of
region or tissue in which changes in turnover are taking place, from
these studies it cannot be concluded whether changes in collagen
turnover of tendon-related tissue or
intramuscular connective tissue occur. The use of the
microdialysis technique has recently been applied to the
peritendinous space of the
Achilles tendon in runners before, immediately after, and 72 h after
36 km of running (386)
(Fig.
5). With this technique it was demonstrated that acute exercise
induces changes in metabolic and inflammatory activity of the
peritendinous region (386).
In addition, acute exercise caused increased formation of
type I collagen in the recovery process, suggesting that acute
physical loading leads to adaptations in non-bone-related collagen
in humans.
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FIG. 5. Collagen type
I synthesis and degradation in response to acute and chronic
exercise. Interstitial concentrations of carboxy-terminal propeptide (PICP)
and telopeptide region (ICTP) of type I collagen in peritendinous
tissue of human Achilles tendon.
Microdialysis was used to obtain tissue concentrations, and PICP was
used as an indicator for collagen type I synthesis, while ICTP was a
marker for degradation of type I collagen. The top
panels show values obtained in highly trained individuals before
(rest), immediately after 36 km of running (recovery), as well as 72 h
after termination of exercise (72 h). Both PICP and ICTP
decreased initially after exercise, and a marked increase in
collagen synthesis was detected 72 h after exercise. The bottom
panels show values obtained in healthy humans before, as well as
4 and 11 wk into daily physical training. Both synthesis and
degradation increased after 4 wk of physical training, whereas after 11
wk only the collagen synthesis, and not the collagen degradation,
was chronically elevated. *Values significantly (P < 0.05)
different from basal levels (rest). [Adapted from Langberg and
co-workers (382,
386).]
| |
Furthermore, when type I collagen synthesis and degradation in
connective tissue of the Achilles peritendinous space was
studied before and after 4 and 11 wk of
intense physical training, an adaptive response of the
collagen type I metabolism of
the peritendinous tissue around human Achilles tendon was found
in response to physical training (382)
(Fig.
5). The increase in interstitial concentrations of
PICP rose within 4 wk of training and remained thereafter
elevated for the entire training period, indicating that collagen
type I synthesis was chronically elevated in response to training. As
blood values for PICP did not change significantly over the training
period, it is reasonable to suspect that the increased collagen type
I formation occurs locally in non-bone tendon connective tissue
rather than reflecting a general rise in formation of
collagen type I throughout the body (382).
Also, tissue ICTP concentrations rose in response to training, but
this rise was transient, and interstitial levels of
ICTP returned to basal levels with more prolonged training. Taken
together, the findings indicate that the initial response to training
is an increase in turnover of
collagen I, and that this is followed by a predomination
of anabolic processes resulting in an
increased net synthesis of
collagen type I in non-bone connective tissue such as tendons (382).
The pattern of stimulation of
both synthesis and degradation with the anabolic process dominating
in response to exercise in tendon-related connective tissue is a
pattern that is in accordance with events occurring with muscle
proteins in response to loading (540).
As individuals in the training study (382)
were training on a daily basis, it can be difficult to differentiate
effects of each bout of acute exercise from the chronic
training adaptation. Previous acute bouts of
exercise will influence the outcome of
each subsequent one. This probably explains why highly trained
runners (training up to 12 h/wk) in one study had high basal levels
of interstitial levels of
PICP (386).
Thus it cannot be excluded that the effect on collagen metabolism
found during a program with daily training simply reflects an effect
on collagen formation from the last training bout, rather than
chronic effect of training.
On the basis of these findings it can be concluded that
both an increased collagen turnover is observed in response to
training and that with prolonged training a net synthesis
of collagen type I is to be expected.
Whether a net synthesis of
collagen type I is transformed into morphologically detectable
increases in tendon size is far from clear. However, in accordance
with this view, it has been demonstated in animal models that
training results in enlargement of
tendon diameter (74,
605,
689).
Furthermore, recent cross-sectional observations in trained runners
versus sedentary humans have shown that magnetic resonance
imaging (MRI)-determined Achilles tendon cross-sectional area was
enlarged in trained individuals compared with untrained controls (553).
It can also be speculated that training initially results in an
increased turnover of collagen type I to allow for
reorganization of the
tissue and that more prolonged training results in a net increase in
tendon tissue and probably alterations in tissue strength.
No clear dose-response relationship between type and amount
of training and adaptive responses of
collagen formation exists, but in equine tendon it has interestingly
been found that in tendon subjected to low-level repetitive stress
(extensor tendon) the collagen level is higher that in flexor tendons
subjected to high stress (497).
This indicates that intensity and loading pattern including recovery
periods between training bouts likely play an important role
in adaptation of ECM. Stretch-induced hypertrophy
of chicken skeletal muscle has been shown to
increase muscle collagen turnover using tracer methods (389),
which is in accordance with the present findings on humans in which
collagen synthesis increased markedly at the beginning of
training. From studies by Laurent and co-workers (387–389),
it was concluded that a large amount of
newly synthesized collagen was wasted, resulting in disproportionate
high collagen turnover rate compared with the magnitude of net
synthesis of collagen. Likewise, in human muscle,
type IV collagen degradation, as indicated by an increased MMP-2,
increased over a period of 1
year with electrical stimulation of
spinal cord injured individuals, without any detectable change in
type IV content, indicating an increased collagen turnover rate with
no or very little net synthesis (342).
Measuring the racemization and isomerization of its
C-telopeptide (CTx) has been used to determine collagen type I
turnover. As these processes are coupled to protein turnover it is
likely that they reflect an index of
collagen turnover (237).
With this method it has been shown in human cadaver tissue that
tissues like tendon and ligament have a turnover rate comparable
to that in bone, and that the turnover of
collagen type I is in fact quite pronounced in skeletal muscle (237).
These data agree with studies using radiolabeled
proline/hydroxyproline in animals showing a relative turnover (3%)
of collagen per day in skeletal muscle
(389).
The present studies in humans and animals support the idea of a simultaneous activation
of both formation and degradation in
collagen of both muscle and tendon tissue in response
to loading. Interestingly, for type I collagen in tendon,
timewise this is followed by a more pronounced imbalance in favor
of formation and resulting in a net
collagen synthesis, whereas in muscle, type IV collagen does not seem
to reveal any net synthesis. In addition to an increased turnover
of collagen, indirect evidence for
loading increased both synthesis and degradation rates has been
demonstrated also for non-collagen components of the
ECM (53,
537,
549).
An important step in collagen type I formation is the enzymatic
regulation by procollagen C-proteinase (PCP) of the
cleavage of PICP and PINP of
procollagen to form insoluble collagen (311).
It has been demonstrated that mechanical load can enhance the
expression of the PCP gene, but not of the
procollagen C-proteinase enhancer protein (PCPE) in dermal
fibroblasts (498).
In addition to this, it was shown that both the synthesis and the
processing of procollagen were enhanced by loading in vitro.
This effect was demonstrated to be specific as non-collagen protein
synthesis in that study was not elevated (498).
Furthermore, an enhanced processing of
procollagen to insoluble collagen was found, as evident by a larger
increase in the actual amount of
insoluble collagen produced compared with the increase in
procollagen synthesis. Interestingly, in that study it was
demonstrated that the above-described changes only occurred if cells
were in tissue cultures containing TGF- or serum (498),
indicating that mechanical loading by itself is not able to cause
changes unless certain growth factors were present.
D.
Immobilization and Collagen Turnover
In contrast to physical loading, immobilization of rat
hindlimb leads to a decrease in the enzyme activities of
collagen biosynthesis in both skeletal muscle and tendon (569,
570),
which suggests that the biosynthesis of the
collagen network decreases as a result of
reduced muscular and tendinous activity (181).
The rate of the total collagen synthesis depends mostly on
the overall protein balance of the
tissue, but it seems to be positively affected by stretch in both
muscle and tendon (569,
570).
Changes in the total collagen content of
muscle, measured as hydroxyproline content, are usually small or
absent during immobilization lasting for a few weeks, which is
probably due to the turnover rate of
collagen (257).
Collagen expression during immobilization has been shown to be at
least partially downregulated at the pretranslational level (11).
The mRNAs for type I and III collagens were already decreased after 3
days of immobilization, whereas stretch
seemed to counteract this decrease (11).
The content of type IV collagen was also reduced as a result
of immobilization (12).
In other studies of rats, amounts of
collagen in skeletal muscle were studied in response to
immobilization at increasing muscle length to cause either atrophy or
hypertrophy (569).
Whereas P-4-H decreased and proteolytic enzyme activity increased
in shortened muscle, no increase in P-4-H or GGT could be
detected in lengthened muscle (569).
Electrical stimulation could, at least in some muscles, counteract
the immobilization-induced drop in muscle mass together with the
decrease in content of hydroxyproline and collagen-related
enzyme activities (571).
To some surprise, it was found that denervation of
muscles in rats resulted in an elevation of
hydroxyproline content and in P-4-H and GGT activities of
muscle (571).
Although non-collagen proteins of the
atrophying muscle were degraded at a high rate during denervation,
this could not solely explain the rise in collagen content and enzyme
activity with denervation. In tendons of
immobilized and denervated muscle, activities of
collagen-synthesizing enzymes fell during immobilization in the
shortened position but were unaffected when immobilized in the
lengthened position (571).
This indicated that the regulation of
collagen synthesis to varying mechanical loading possessed
similarities in skeletal muscle and tendon tissue. Further studies
of remobilization of
skeletal muscle after 1 wk of
immobilization in rats showed that activities of
P-4-H and GGT as well as concentrations of hydroxyproline (HP) rose within
days, whereas remobilization exercise did not cause any rise in
tendon P-4-H or GGT (318).
This could imply that although activity can activate collagen
synthesis in both tendon and skeletal muscle, a higher activity
is needed to stimulate tendon than muscle.
|
V.
DEGRADATION OF CONNECTIVE TISSUE IN TENDON AND SKELETAL
MUSCLE: EFFECTS OF CHANGES IN MECHANICAL LOADING
|
Degradation
of collagen represents an obligatory step
of turnover and of
remodeling of connective tissue and during mechanical
loading of fibroblasts and extracellular matrix
structures. Both intracellular and extracellular degrading pathways are
present, using either lysosomal phagocytosis or ECM proteinases,
respectively (193)
(Fig.
4).
A. MMPs
Collagen degradation is initiated extracellularly by MMPs (or
matrixins), which are presented in tissues mostly
as latent proMMPs (38,
49,
475).
There is evidence to support that MMPs [and tissue inhibitors
of matrix
metalloproteinases (TIMPs)] are not involved to a major degree in the
intracellular lysosomal phagocytosis, but function extracellularly (192).
The collagen degradation processes are well described in situations
with rapid remodeling, e.g., inflammation or tissue damage (140,
295,
436),
but its role during normal physiological stimulation
to increase tissue turnover like after mechanical loading is
not known (192).
Whereas collagenases (MMP-1 and MMP-8) traditionally are thought
primarily to initiate degradation of
type I and III collagen and thus should be most relevant for tendon,
gelatinases (MMP-2 and MMP-9) mainly break down nonfibrillar type IV
collagen and other compounds of the
ECM. Although some preference for the different MMPs with regard to
collagen types exists, the specificity of
certain MMPs toward collagen types may be less than thought so far.
As an example, MMP-2 can also degrade type I collagen (13),
most likely in a two-step fashion (500),
and the whole role
of MMPs on tissue matrix
metabolism seems far more complex (475).
MMPs are produced from endotenon fibroblasts and intramuscular
matrix fibroblasts, although the secretion
is somewhat lower than that of
synovial cells (526).
Immobilization leads to an increase in MMP expression at both
preand posttranlational levels, suggesting accelerated collagen
breakdown, which can be partially prevented by stretching procedures.
The regulation of MMPs in relation to exercise remains to be
fully understood, but it is known that specific integrins (21) are regulators of the
MMP-1 gene expression in fibroblasts cultured in
contracting-retracting collagen gel (475).
Furthermore, it is known that MMP-1 expression can be modulated by
growth factors, inflammatory cytokines, and cytoskeleton-disrupting
drugs like cytochalasin D. However, the role
of contraction and stress relaxation
has not been evaluated. In a retracting collagen gel, MMP-1 is
expressed as a result of the tension on the tissue (369)
and mediated through 21-integrins (545).
Increased fluid flow has in vitro been shown to increase the
expression of both MMP-1 and MMP-3, together with an
activation of interleukin (IL)-1 and cyclooxygenase (COX)-2 genes (29,
32).
Mechanical stress relaxation stimulated MMP-1 gene expression has
more recently been shown to depend on de novo protein synthesis,
although it occurs independently of the
activation of an IL-1 autocrine feedback loop (370,
371).
Mechanical stretching is known to elicit an increase in MMP gene
expression (29,
32)
without any obligatory rise in collagen type I expression or
indication of changes in inflammatory meditors in vitro.
However, the IL-1 was able to induce marked increases in MMP expression, and
a synergistic effect of IL-1 and stretching was observed (29,
32).
This fits with findings on human tendon tissue where IL-1 and oncostatin caused an increased production of
MMP-1 (117).
In lung fibroblasts, stretching is found to increase activation
of MMP-9 directly in the absence of any
inflammatory mediators (617).
Interestingly, shear stress elicited by fluid pressure on rabbit
tendon fibroblasts elicits expression and release of
MMP-1 and -3, in the absence of any
change in intracellular calcium concentration (29,
32).
MMP-2 and -9 are known to be overexpressed and present in higher
amounts in patients with inflammatory myopathies (329),
which may increase ECM degradation and thus facilitate lymphocyte
adhesion (132).
Furthermore, the attachment of
type I collagen to cultured fibroblasts upregulated MMP-2 and MMP-9
production, an effect that was blocked by dexamethasone (547).
Finally, MMP-2 is colocalized with integrins placed in vessels (102),
and MMP-mediated proteolysis of
capillary basement membrane proteins is important for physiological
angiogenesis responses to chronic loading of
skeletal muscle, and increased production of
MMP-2 and MT1-MMP is crucial for new capillary formation during
mechanical stimulus (251,
252,
641).
Taken together, several of the
exercise- and training-related adaptations are coupled to processes
that are found to involve MMP responses (409).
Recently, it has been demonstrated that acute exercise resulted in
elevated interstitial amounts of
MMP-2 and MMP-9 in human peritendinous tissue (346),
which supports the view that MMPs (and their inhibitors) play a
role in ECM adaptation to exercise in
tendon tissue.
B. TIMPs
TIMPs inhibit MMP activities (198).
Of the four TIMPs so far identified,
TIMP-1 and TIMP-2 are capable of
inhibiting activities of all
MMPs with a preference for inhibiting MMP-2 and MMP-9, respectively.
Pro-MMP-2 is upregulated both at the pre- and posttranslational level
after a single bout of exercise, suggesting an increase in
the collagen degradation (343,
345).
In line with this, stretch-relaxation on dermal fibroblasts
results in increased activity of
MMP-2 through integrin-mediated pathways (369,
372).
As mentioned previously, increased MMP activity and thus enhanced
degradation of collagen often
parallels the stimulated activation of
collagen synthesis (345).
Interestingly, TIMPs are often
activated together with MMPs in response to physical activity (345),
indicating simultaneous stimulation and inhibition of
degradation. Rather than considering this as a competitive action, it
is likely that MMP activity precedes TIMP activity, and thus TIMP
serves as regulators of degradation termination to ensure a
limited amount of degradation. To support further that
an integrated response of MMPs and TIMPs exist, TIMP-2 has
been shown to be important for an activation of
pro-MMP-2 in vivo (670).
TIMP-1 has been found to be correlated with ICTP in patients with
cancer, indicating activity in and control of
collagen degrading pathways (701).
|
VI.
STRUCTURE OF EXTRACELLULAR MATRIX IN TENDON AND MUSCLE: RELATION TO
MECHANICAL AND VISCOELASTIC PROPERTIES |
A. Extensibility
of Tendons
Tendons vary in their ability to stretch, from 1–2% of lengthening of the
animal extensor carpi radialis, to 3–4% of
lengthening of the flexor carpi ulnaris tendon, and up to
16% of elongation of the
rabbit Achilles tendon (403).
Human cadaver data imply that the maximal elongation of
human tendon is up to 5–6% when passively stretched (413).
In association with this, the aponeurosis of the
adjacent muscle generally displays a larger mechanical excursion
compared with free tendon under passive stretch (10–12%) (403).
Although indicative of the
viscoelastic potential of the tissue when challenged to
passive loading, these findings do not take into account the in vivo
characteristics during muscular activity. Some studies have shown
that the free tendon and aponeurosis of the
cat triceps surae have comparable mechanical properties during
isometric contraction (585,
629).
In contrast, the stiffness of the
aponeurosis is found to be less than that of
free tendon during contraction, whereas others have found the
reverse, namely, that tendon strain was 2% while aponeurosis strain
was 8% during passive loading (403)
(Fig.
6). Such findings do not, however, take into account that during
muscle contraction in vivo in humans it is likely that the
contractile apparatus of the muscle will limit the excursions
of the aponeurosis. Attempts to separate
aponeurosis movement and free tendon movement in vivo have shown
varying results (296,
422).
Some studies found no difference between Achilles tendon and the
adjacent aponeurosis (225,
226,
355,
356).
However, in those studies the Achilles tendon was defined as the free
tendon plus the soleus aponeurosis. In a study on tibialis anterior
free tendon, this was only strained 2%, whereas the aponeurosis was
strained up to 7% during submaximal isometric contraction (422).
Somewhat in contrast, it has been shown for the human Achilles tendon
that the strain of free tendon was six- to sevenfold
greater than that of the aponeurosis during intense
isometric calf muscle activation (427)
(Fig.
6). The difference between studies of
viscoelastic properties of
the free tendon and skeletal muscle aponeurosis can both be
accounted for by measurement limitation, such as accounting for
antagonist activity, joint rotation, and the fact that the
methodology is limited in its ability to observe three-dimensional
phenomenon (85,
425).
The pronounced difference between the strain in free tendon and the
aponeurosis in the human Achilles region suggests that their
functional role during force transmission differs.
It is on this background suggested that free tendon permits for
storage and release of energy, while the aponeurosis ensures
effective transmission of
contractile forces.
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FIG. 6. Load-strain
relationship for tendon and muscle aponeurosis during passive and
active muscle contraction. Top: determination of load-strain on frog semitendinosis
during passive loading of structures up to a tension equal to
maximum active isometric tension (Po). The relationship
for tendon, bone-tendon junction (BTJ), and aponeurosis is given,
and passive loading expressed in %Po. Note that the
strain of the aponeurosis by far exceeds that
of the tendon. Bottom: tendon
load-strain on human Achilles tendon and triceps surae aponeurosis
determined on human tendon/muscle with ultrasonography during calf
muscle contraction. Note that in the active, contractiing state, the
strain of the free tendon is severalfold
higher than that of the adjacent aponeurosis. [From
Lieber et al. (403)
(top) and Magnusson et al. (427)
(bottom), with permission.]
| |
B.
Repetitive Loading and Tendon Properties
Several in vitro systems for determination of
cellular responses to mechanical tensile stress are available. One
way to study mechanical loading of
fibroblasts is to seed cells upon a flexible substrate that allows
for easy control of strain, whereas actual forces put
upon the individual cell cannot be accurately quantified (221,
418).
Another method to grow fibroblasts is in a native three-dimensional
collagen matrix in which they attach and pull on
collagen fibrils. This latter method allows for determination
of tensile force developed, whereas strain is more
poorly defined (221).
It is clear that fibroblast cultures subjected to biaxial mechanical
loading often result in uneven strain and loading
across the plate, and this model thus only obtains results that
represents a mean of the
different ranges of movements (498).
The in vitro systems evidently have major advantages with regard
to localized measurements and the possibilities for intervention;
however, it still represents a simplified system that does not
always encompass all the growth factors that are needed in the
transformation phase from mechanical loading to synthesis of ECM proteins like collagen.
Tendons respond to mechanical loading, and animal studies have
provided some evidence that endurance training will influence
their morphology and mechanical properties (106,
190,
355,
652,
687,
689).
In rabbits, it has been shown that the load-deformation curve
of the Achilles tendon was unaffected by 40 wk
of training, which implies that no
structural properties were influenced by the training (652).
However, the same group also showed with similar training that the
posterior tibialis tendon displayed a load-deformation curve that was
altered without any detectable change in tendon volume or mass, which
suggests that the mechanical loading resulted in qualitative rather
that quantitative changes (653).
Somewhat in contrast, 12 wk of
training in swines increased both load-deformation and stress-strain
properties of digital extensor tendons, together
with an increase in the cross-sectional area (CSA) and total collagen
content of the tendon (687,
689).
This supports the view that both structural as well as mechanical
properties are improved with training. Interestingly, in a similar
model, this was shown to be the case only after 12 mo, but not
after 3 mo of training, and the shorter training period in
fact reduced the tendon size (687).
In support of this pivotal adaptation
of tendon morphology, training studies on horses
revealed that 5 mo of
training did not influence the CSA of the
Achilles tendon, whereas 18 mo of
training increased it by 14% (74,
502–504).
Finally, in rats the CSA of the
Achilles tendon reduced after 1 mo, but increased after 4 mo
of training (505).
In both the latter studies a quasi dose-response relationship was
obtained in that low-intensity training did not change the tendon
morphology, but intense training did so. In two additional studies,
training did not alter the dry weight of the
patellar tendon of rats (638)
or of chicken Achilles tendon (153).
A study in turkeys showed that despite only a minimal change in
tendon CSA area after training, the mechanical properties changed and
an increased tendon stiffness was found (106).
This would theoretically yield a larger amount of
stored energy in the tendon and thus enhance locomotion economy. This
would, however, require a larger force on the tendon, which is
unlikely at the same absolute running speed, and it was therefore
suggested that the altered properties could contribute to a larger
tendon resistance towards material fatigue and subsequent
damage.
Somewhat in contrast to other studies, running in mice resulted in
unchanged tensile strength of
patellar tendon (330),
but it has to be acknowledged that the mice were not adult, as
has been the case in other studies (652,
687,
689).
Finally, rat Achilles tendon was found to increase tensile strength
and stiffness after 30 days of
training (655).
In addition to the classical stress-strain curves, attempts have been
performed to address cumulative damage and fatigue development in
tendon tissue that is repeatedly loaded with forces that are below
the ultimate tensile stress. It was found that time-to-rupture among
tendons was similar when tendons were subjected to a load that
corresponded to the maximal voluntary contraction of
their corresponding muscle (324–326).
This would mean that all tendons appear similarly prone to fatigue
ruture, and it is suggested that any CSA of a
tendon is coupled to the achievement of a
certain stiffness.
Only one study has tried to compare strength and endurance training,
and in rats they found that 38 wk of
training was associated with an age-related decline in ultimate
load-to-failure that was counteracted by swimming training, but no
effect was seen in response to strength training (595).
It could be argued that the strength protocol was limited in that
study and that a further major drawback was the lack of any
determination of tendon area or volume, which
precluded the evaluation of any
quantitative versus qualitative effect of
training. Only few studies have addressed the effect of
training on intratendinous structures (159),
and although one very early study did not demonstrate any
intratendinous fibril increase as a result of
training in rats (292),
a subsequent study demonstrated increased fibril diameter after
training (453,
454).
In the horse, an 18-mo training program did not result in any
significant change in collagen fibril diameter of the
deep flexor tendon of the horse (502,
504).
As horses have been shown to increase the CSA of the
tendon in response to such prolonged training (74),
it indicates that the number of
collagen fibrils was increased. This was also found in one study
after 10 wk of training (454),
and furthermore, one study demonstrated more densely packed and
aligned fibrils as a result of
training (655).
It has been shown with ultrasonography in humans that the compliance
of the muscle vastus lateralis aponeurosis-tendon
complex was lower in long-distance runners compared with that in
untrained subjects (355).
It was stated that this allowed the complex to store energy and reuse
it more efficiently in runners compared with sedentary counterparts.
Somewhat in contrast to this, no difference in compliance was found
between sprinters and control individuals with regard to both the
quadriceps and triceps surae tendon-aponeurosis complex (356).
This is interesting, since sprinters are a group of
athletes that would need capacity to reuse elastic energy. The same
authors found, however, that 8 wk of
isometric strength training, but not 4 wk, did increase the stiffness
of muscle vastus lateralis in humans,
indicating an effect of
training duration on tendon-aponeurosis properties (354).
However, it has to be remembered that the ultrasonography method used
in those studies cannot clearly separate the tendon properties per se
from those of the combined tendon-aponeurosis
complex.
The highest tolerable tensile load of a
tendon is known to depend on its CSA in relation to integrated
fascicle CSA of the adjacent muscle, and this
relationship varies between tendons in different species but also
between tendons in a given individual (63,
64,
325,
326,
512).
In this respect it is interesting that a cross-sectional study found
that the CSA of long distance runners was 20–30%
larger than untrained controls, while the load-deformation curve
of the triceps surae aponeurosis-tendon complex
did not differ (553).
When the ratio between muscle and tendon area (multiplied by 0.3 MPa
as a chosen number for maximum isometric stress, Ref. 325)
was related to a certain load, differences in fatigue resistance to
failure were seen between different tendons (326)
(Fig.
7). Interestingly, if the individual tendons were subjected to
individual loading dependent on the capacity of the
relevant adjacent muscle, the time to rupture was similar between
tendons (326).
This implies that fatigue and resistance to rupture are coupled to
the tendon-loading pattern, which was shown when high-stress and
low-stress tendons in sheep develop their functional capacity matched
the working demands of the tendon (510).
If we combine this with the data obtained in humans of
varying training degree, the larger CSA of the
trained tendon results in a lower stress on the tendon during maximal
isometric force in trained compared with untrained individuals (553),
and thus provides a potentially more injury-resistant tendon
(Fig.
8). The safety factor (fracture stress set at 100 MPa divided by
the stress during intense activity) has been found to be 8 in general for most tendons (325).
It was shown in humans in vivo that the safety factor was only 2–3
during maximal isometric contraction (431).
Therefore, tendon hypertrophy would seem helpful in counteracting
overload and prevention of
ruptures. These data fit with previous observations on old
individuals where there is a tendency toward larger CSA of the
well-trained individuals (314,
426).
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FIG. 7. Tendon time
to rupture in animal tendons during mechanical loading. Top:
time to rupture in wallaby limb tendons when subjected to a constant
stress of 50 MPa. Linear regression with 95%
confidence intervals are given. Bottom: time to rupture at
stresses related to those experienced in life. "Stress-in-life" is
defined as the area ratio between muscle cross-sectional area (CSA)
and the adjacent tendon CSA, and multiplied by 0.3, to illustrate a
more relative comparison between tendons. Interestingly, when
stress-for-life is used, time to rupture is close to identical for
all tendons measured (4 h). This would indicate that all tendons will have a need
for structural adaptation toward loading to counteract overloading
and subsequent injury. [From Ker et al. (326).]
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FIG. 8. Mechanical
loading of physically trained and untrained
human tendon. Top: cross-sectional area (CSA) of the Achilles tendon in habitual
runners and nonrunners (control) (left) as determined from
magnetic resonance imaging 6 cm above the calcaneal insertion
(right). Runners showed significantly larger CSA than
controls. Middle: load-deformation curve during graded
isometric triceps surae contraction, obtained by ultrasonography on
human Achilles tendon. No statistical significant difference was
found between groups. Mean ± SE is given. Bottom:
stress-strain relationship of the human Achilles tendon in
runners and sedentary controls. Mean ± SE is given. The fact that
runners have a higher CSA contributes to the significant lower
maximal stress in runners (triangles) compared with controls
(circles) and may thus indicate a lower relative stress on the
tendon in well-trained athletes compared with untrained
counterparts. [Modified from Rosager et al. (553).]
| |
Sonographic evaluation of the
Achilles tendon has shown that the CSA of the
tendon is larger in individuals with an active history of
physical training than in sedentary counterparts (700).
Most likely, increase in tendon CSA in humans requires very prolonged
anamnesis of training, as 6 mo of
recreational running training in previously untrained individuals was
not sufficient to increase the CSA of the
Achilles tendon (428).
In muscle, the passive movement of the
perimysium is viscoelastic but does not involve any major
reorientation movements of
collagen fibers in a proteoglycan matrix
(519).
Rather, the viscoelastic pattern to stretch depends on relaxation
processes within the collagen fibers themselves or at the
fiber-matrix interphase. In tendon it has
been shown that the molecular packing of
collagen is extended upon stretch in the rat tail (215,
460).
This could be due to molecular straightening and gliding
of collagen molecules. However, the
strain within collagen fibrils is always smaller than stretching
of the entire structure (i.e., the tendon),
which implies that additional gliding occurs at the interfibrillar
level. That other structures than the collagen fibrils themselves
are involved in tension resistance and subject to injury is
supported by the demonstration that fibrils do not run through
the entire length of a
tendon but are largely dependent on cross-linking (630,
632).
In line with this, it has been shown that shorter specimen samples
of tendons are more resistive to rupture when
determining time to failure towards a given test stress, indicating
that strengthening structures are added and increasingly important
when longer tendons are studied (669).
The cross-linking between parallel collagen molecules includes both
aldimine and ketoimine, of
which the former dominates during development of
tendon (47,
48).
Later on, other cross-links bind collagen molecules together
including pyridinoline, and with aging a nonspecific cross-linking
through glycation comes into play (54).
Only a few studies have looked at the importance of
these cross-links, but it has been demonstrated that chemical
preparation of tendon to reduce numbers
of almidine cross-links was found to increase
tendon strength and diminish stress relaxation, implying that these
links are involved in the stress relaxation (160).
C. Aging,
Disuse, and ECM
With aging of connective tissue or in diseased states with
elevated glucose levels (e.g., diabetes) the nonspecific
cross-linking mediated by condensation of a
reducing sugar with an amino group and result in accumulation
of advanced glycation end products
(AGEs), in tendon tissue (297,
535,
587).
It has been shown that glycated tendons could withstand more load and
tensile stress than nonglycated tendons (535),
but the tissue gets stiffer (648).
In chondrocytes it has been demonstrated that not only is a
relatively low turnover of
collagen in the tissue a prerequisite for the formation of
AGEs (648),
but that the presence of AGEs feedback to reduce both
collagen synthesis and MMP initiated collagen degradation (162).
When biochemical markers (pentosidine and fructosamine) of
AGEs are correlated to microscopic determination of
collagen fibrils in the rat tail tendon, it can be shown that high
amounts of AGEs are coupled to tight assemblence and
fusion of fibrils, thus displaying larger collagen fibril
diameters than in the healthy (293,
489).
Likewise, the morphological and biochemical picture of
tendons in which AGEs were induced by glucose incubation were
strikingly similar to tendons from diabetic animals (361,
489).
The accumulation of AGEs with aging thus indicates a
stiffer and more load-resistant tendon and intramuscular ECM
structure, but on the other hand reduces the ability to adapt to
altered loading, as the turnover rate of collagen is markedly reduced (360).
In addition to this, it has been shown that AGEs upregulate
connective tissue growth factor (CTGF) in fibroblasts that thus favor
the formation of fibrosis over time in elderly
individuals and patients with diabetes (636).
It is well described in animals that the average fibril diameter
increases during development (118,
496,
497)
but declines with aging (476)
and disuse (477).
The effect of training on this is variable (453,
501–504).
Somewhat in contrast to animal data, the overall CSA of the
Achilles tendon is larger in elderly compared with younger
individuals (426).
The phenomenon may reflect a compensatory increase in ECM to lower
stress on the tendon due to age-related decline in tendon quality and
thus in maximal tolerable load (426).
This is interesting, since there are observations of
reduced expression and synthesis of collagen in aging fibroblasts (47,
124,
239).
In addition, covalent intramolecular cross-links are known to
increase the elastic modulus, and reduce strain to failure, but do
not influence rupture stress (47,
168,
624).
This phenomenon is more pronounced in high-load bearing flexor
tendons compared with low-stress extensor tendons (47,
73).
Interestingly, cross-linking and stiffness are increased with aging,
whereas endurance training counteracts these phenomena (244).
The same counteractive effect is found in elderly with low-load
resistance training (357),
but not found with very intense strength training (538).
The fact that in association with increased tendon stiffness
with aging, bone mineral density is decreasing, which might
explain why older individuals are more prone to get avulsions
of the bone rather that tendon ruptures
compared with younger counterparts (692).
D.
Integrated Muscle-Tendon ECM Properties
In vivo determination of
viscoelastic behavior of a stretched muscle-tendon unit (423,
424).
In the absence of any detectable electromyelogram
(EMG) activity in the passively stretched muscles, and during dynamic
stretching a curvilinear increase in resistance towards stretch was
found, whereas a nonlinear stress relaxation response declining the
resistance by 25–35% was demonstrated over the 45 s of
static loading phase (433).
This effect has no influence on subsequent stretch procedures (424,
435,
443).
Furthermore, when a series of
stretching procedures was carried out, it was found that this acutely
lowered the stiffness and storage of
passive energy during dynamic stretch, but that the effect vanished 1
h after stopping the stretching regimen (432–434).
This supports the notion that passive stretching of
muscle-tendon has no chronic effect on viscoelastic properties
of the tissue. If this is the case,
chronic stretching of muscle tendon unit in association
with physical training should not cause any altered passive
properties of the muscle-tendon unit, and thus challenge
common clinical belief (227).
In an investigation where subjects performed repeated stretching
exercises twice daily for 3 wk, no change in passive properties
of the muscle-tendon unit was found. It
was demonstrated that the maximal flexibility was improved by the
training, but this was achieved at the expense of a
high resistance to stretch (434).
At present it is unknown what mechanism lies behind this phenomenon.
Evidently, the passive properties interplay with active muscle
contraction in a very complex way. In isolated animal
muscle-aponeurosis-tendon preparations it has been shown that rapid
elongation of the passive tendon structure takes
place upon muscle stimulation and shortening (404).
This potentially creates a scenario where muscle fibers shorten at a
high velocity and lower force development in the initial phase
of contraction. When the passive structure
such as tendon subsequently reaches its point of
increased resistance towards stretch, the shortening velocity
of the muscle will markedly decrease,
and thus allow for a higher force output from muscle (404).
Perhaps, depending on tissue qualities, tendon and/or muscle will be
more fragile toward rupture at high loading, and that muscle rupture
can occur at a late time point in the contraction. In addition,
surgical transfer of tendon in human arm has been
demonstrated to influence functional muscle-tendon performance
dependent on the length at which the muscle-tendon complex is
surgically inserted (219).
Thus an attempt to overstretch the tendonmuscle when inserting will
cause the sarcomere length of the
muscle to be at a suboptimal length with regard to force development
(219).
|
VII.
LOADING AND OVERLOADING OF CONNECTIVE TISSUE STRUCTURES IN TENDON
AND SKELETAL MUSCLE: ROLE OF GROWTH FACTORS
|
The
loading-induced adaptation of ECM
and especially collagen synthesis is dependent on regulatory hormones
and growth factors that together with integrins, cytoskeletal, and
certain ion channels may be responsible for mechanically induced cell
signaling (127).
A role of
growth factors for collagen synthesis is in accordance with findings
that specific circulating growth factors, such as TGF-, IL-1, IL-6, and IL-8, insulin-like growth factor I
(IGF-I), fibroblast growth factors (FGF), NO, prostaglandins,
vascular endothelial growth factor (VEGF), and platelet-derived
growth factor (PDGF), all have positive effects on fibroblast
activation in vitro, when fibroblasts from different tissues
are used (14,
25,
68,
234,
259,
262,
518,
633).
However, in most studies no isolated attempt has been undertaken to
compare this effect with any separate or simultanous role
of mechanical loading upon the release
or synthesis of such growth factors (536).
In one study the importance of
PDGF and mechanical strain was shown to be related to PDGF (51).
Insulin-like growth factors (IGF-I and -II) are known to influence
fibroblast in vitro (7,
8,
10,
51,
121,
576)
and are likely to represent an important growth factor, but their
exact role for collagen synthesis of human tendon and muscle remains to
be elucidated. Furthermore, it has been shown that mechanical loading
induces increased secretion of
TGF-, PDGF and basic FGF (bFGF) as well as expression
of growth factors from human tendon fibroblasts
(598).
Further mechanically loaded fibroblasts result in an increased
gene expression for collagen and ECM components (53).
The effect of specific growth factors or serum components in
combination with mechanical loading on procollagen synthesis and
procollagen propeptide gene regulation indicate a synergy between
signaling pathways with regard to procollagen gene expression and
processing, similar to what has been documented in cardiac
fibroblasts (110).
Interestingly, in a study where tendon grafts used for reconstructive
surgery after ruptured anterior cruciate ligament were analyzed
for content of growth factors, only bFGF was present in
the control situation (359).
Following reconstruction, increased levels of
immunostaining of TGF- and PDGF were noted over the following weeks and were back
to initial levels after 12 wk (359).
Only a few of the most important growth factors for ECM in
tendon and muscle will be dealt with in the following section.
This should, however, not distract from the fact that others
also play major roles
and that even more factors are suggested but remain unexplored. As an
example, the role of NO
and prostaglandins seems clear with regard to mediating mechanical
signaling to the process of
bone formation in the skeleton (134),
and it has been shown that this involves fluid-induced wall-shear
stress (599)
and that osteogenesis acts through COX-2-dependent pathways (708).
This fits with findings of
increased release of prostaglandins from human tendon
fibroblasts that have been mechanically stimulated in vitro (24)
and from human tendon tissue in vivo during mechanical loading (385),
and suggests a role for prostaglandins in the
adaptation of ECM in tendon tissue (543).
A. TGF- and CTGF
TGF- with its three mammalian isoforms
are known to function as modulators of ECM
proteins and to cause induction of
both collagen gene activation and protein formation via Smad
proteins (28,
123,
158,
289,
304,
408,
487,
513,
657,
707).
A coupling between mechanical loading and TGF- has been demonstrated in in vitro studies in a number
of cell and tissue types. In vitro
studies with human cell cultures showed stretch-induced TGF- expression in tendon (598)
and cardiac fibroblasts (558),
smooth muscle cells (249,
488),
and osteoblast-like cells (136,
336).
In cardiac fibroblasts it was shown in vitro that mechanical
loading and TGF- had synergistic effects on procollagen formation, despite
the fact that mechanical loading in the absence of
any growth factors did not result in any stimulation of
collagen formation (110).
Furthermore, both in vivo and in vitro animal studies support a
connection between mechanical strain and TGF- expression (151,
396,
481,
656,
710),
and in cardic fibroblast there is a positive correlation between the
degree of cell loading and the expression
of TGF- (394).
Studies have also shown that mechanically induced type I collagen
synthesis can be ablated by inhibiting TGF- activity (249,
408).
In a human model using microdialysis around the Achilles tendon, it
was found that both local and circulating levels of
TGF- increased in response to 1 h of
running, indicating a role of
this cytokine in the response to mechanical loading in vivo (269,
270).
Furthermore, the time relation between TGF- response and indicators of
local collagen type I synthesis was supportive of a
role of
TGF- in regulation of
local collagen type I synthesis in tendon-related connective tissue
subjected to mechanical loading. In view of the strong relationship between
mechanical loading and TGF- synthesis seen in various cell types (100,
101,
136,
151,
488,
598,
698),
this could indicate a release of
TGF- from tissues that are mechanically activated during
exercise, including bone, muscle, tendon, and possibly cardiac and
vascular tissues. The increase in interstitial fluid concentrations
of TGF- after exercise could indicate a local release of
TGF- in tendon-related tissue, but could also be a result
of increases in TGF- content in the circulating bloodstream. Platelet activation
is known to stimulate TGF- release from the -granule, and prolonged exercise is known to cause platelet
activation (172).
It cannot be excluded that increases in tissue TGF- could be linked to a platelet activation caused by
exercise-induced local tissue damage. This is supported by in vivo
studies that have shown immediate increases in TGF- levels in the rat in response to endurance exercise (100,
233).
TGF- increases in the circulation with exercise (614,
665)
and with daily strength training over 21 days (272).
Taken together, simultaneous rises in TGF- both in circulation as well as locally in the tissue
subjected to loading are compatible with a role
of TGF- in regulation of
synthesis of ECM proteins such as collagen type
I.
In addition to stimulating collagen synthesis with loading,
TGF- has also been demonstrated to increase the expression and
synthesis of other ECM proteins, e.g., PGs (548).
Both aggrecan and biglycan protein content as well as aggrecan,
biglycan, and collagen type I mRNA expression were high after
TGF- administration. Interestingly, in this in vivo model
neither contraction, TGF-, nor a combination thereof
stimulated decorin. From healing models, it is known that decorin can
bind to TGF- and neutralize its biological activity (90).
It is thus likely that decorin requires other growth factors in
combination with loading to be synthesized.
Although TGF- has long been appreciated as a central growth factor in the
formation and maintenance of
ECM, it is thought to be a key player in progressive fibrotic
diseases such as scleroderma and keloid formation, and an independent
role for CTGF was only recently found
in these processes (83,
178,
393,
461,
577).
Although it is known that TGF- can stimulate CTGF synthesis, it has been shown that gene
expression activation of
CTGF is more dependent on mechanical loading than on changes in
TGF- levels (273,
275,
577),
and CTGF is therefore suggested to play a major role
in the accumulation of collagen type I synthesis and other
matrix proteins in mechanically loaded
fibroblasts (577).
Therefore, CTGF also represents an effector substance for the
profibrolytic activity of
TGF- in the maintenance and regeneration of
connective tissue in fibrotic conditions (e.g., formation
of a scar) (393).
TGF- stimulates collagen formation and reduces degradation via
stimulating the TIMPs together with a suppresion of
MMPs, thus favoring an accumulation of ECM
and especially of collagen (182,
493).
In many ways TGF- is considered a "two-edged sword" growth factor, in that an
acute early rise in TGF- is considered physiological after, e.g., mechanical tissue
loading, whereas a prolonged rise in TGF- is associated with uncontrolled formation of
fibrotic tissue (393).
In several models, it has been shown that the TGF- role in fibroblast proliferation and collagen
synthesis appears to be that low levels stimulate whereas high
concentrations of
TGF- inhibit the collagen synthesis and fibroblast proliferation.
It has been shown that inhibition of
fibroblast proliferation at high concentrations of
TGF- may be mediated by autocrine stimulation of
prostaglandin synthesis (PGE2) (444).
A blockade of inflammation in relation to contractile
activity could therefore theoretically lead to unopposed collagen
formation and favor fibrosis, a phenomenon that has been shown in
lung fibroblasts (323).
Alternatively, a blockade of
prostaglandin formation would inhibit the immediate TGF-- and/or CTGF-mediated stimulation of
collagen and lead to suboptimal recovery after exercise-related
tissue injury. In lung connective tissue, TGF- stimulates collagen synthesis, and this can be inhibited
via prostaglandin secretion (518).
Interestingly, this effect of
prostaglandin (PGE2) is most likely due to a blockade
of CTGF transcription, but shows that
both CTGF-dependent and -independent mechanisms exist by which
TGF- and prostaglandin regulate collagen type I expression.
B. FGF
Of the several forms of
FGFs that exist, the one with basic isoelectric point (bFGF or FGF 2)
and to a lesser extent the acidic FGF (or FGF 1) are potent
stimulators of fibroblast proliferation, collagen
synthesis, and formation of
granulation tissue (264).
The effect of bFGF has mainly been studied in relation to
tendon injury where healing processes have been shown to be
positively related to administration of
bFGF (120,
176).
It has also been shown that expression of
bFGF is present in normal intact tendons, but markedly upregulated in
injured tendons (121).
This upregulation was observed both in tenocytes within the tendon as
well as in tendon sheath fibroblasts and infiltrating inflammatory
cells. Mechanical loading has been shown to induce FGF release in
vitro from skeletal muscle cells, and growth of
these was inhibited by administration of a
neutralizing antibody toward FGF activity (138).
Somewhat in contrast, a study using cyclic mechanical stretching
of human tendon fibroblast for 15 min could not
demonstrate any synthesis of
bFGF above that of the control fibroblasts (598).
However, it must be acknowledged that the concentration in their
model increased by 10-fold over time, but despite this, no
statistical difference could be detected between control and
mechanically stimulated fibroblasts (598).
Interestingly, bFGF has been found to stimulate connexin43, which is
known to be located in gap junctions between fibroblasts in
tendons (169).
This suggests a role of FGF
for intercellular communication in relation to converting mechanical
loading to biochemical activity leading to restructuring
of the ECM. Part of the
effect of FGF is mediated via PDGF, which is known to
stimulate procollagen synthesis of,
e.g., pulmonary artery fibroblasts (79),
and it has been demonstrated that a combination of
bFGF and PDGF results in further increased DNA synthesis in synovial
fibroblasts (255).
Finally, in chondrocytes, bFGF has been found to inhibit the
effect of IGF-I and TGF- on synthesis of type II collagen (165).
C. IL-1 and IL-6
The cytokine IL-6 is known to be released from fibroblasts (642)
and has been suggested to be involved in collagen metabolism in
bone tissue (246).
IL-6 is produced by cells of the
ostoblast and osteoclast lineages and has recently been shown to
enhance both the expression and protein content of
IGF-I in osteoblasts (213).
This was not affected by IL-6 only, but required the presence
of the soluble IL-6 receptor and was most likely
dependent on prostaglandin to be effective (499).
In tendon, the secretion of
IL-6 has been found to be significantly induced by 15 min
of cyclic biaxial stretching in vitro and remained
elevated for at least 8 h (598).
In humans experiments have been performed using the microdialysis
technique, where IL-6 concentrations were obtained simultaneously in
plasma, skeletal muscle, and peritendinous connective tissue in
response to prolonged exercise (380).
It was demonstrated that exercise-induced increases in peritendinous
interstitial concentrations were 100-fold larger than in plasma and
7- to 8-fold larger than interstitial concentrations in skeletal
muscle. This demonstrates that connective tissue around the human
Achilles tendon produces significant amounts of
IL-6 in response to prolonged physical activity and contributes to
exercise-induced increases in IL-6 found in plasma. This does not
exclude major contributions of
skeletal muscle to changes in plasma, since it has been demonstrated
that skeletal muscle releases IL-6 with exercise (505,
607,
685).
However, this release from an exercising extremity somewhat
overestimates the amount of
IL-6 that is produced in the skeletal muscle cells themselves (491).
It is therefore likely that the discrepancy can be accounted for by
the release of IL-6 from, e.g., intramuscular connective
tissue, adipose tissue, or vasculature within the muscle. In
accordance with this, cell types known to be located between
muscle fibers have been shown to secrete IL-6 (184,
220,
337,
456).
Furthermore, it has been shown that in adipose tissue only 10%
of the total IL-6 release was origining from the
adipose cells themselves, whereas 90% came from
collagenase-sensitive ECM (220).
Finally, IL-6 mRNA was elevated in fibroblasts and macrophages
rapidly after an experimentally induced muscular injury (315).
IL-6 can stimulate fibroblasts to increase the production of collagen and glycosaminoglycans,
hyaluronic acid, and chondroitin sulfates, but it only partly
mediates the role of
IL-1 on the fibroblast (177).
In epitenon fibroblasts, microwounds have been shown to result in
local release of TGF-, IL-2, and IL-1 cytokines, and this was found to positively
affect cell adhesion, proliferation, fibronectin deposition, and time
to wound healing (686).
In gingival connective tissue, the levels of
IL-1, IL-6, and IL-8 were higher in inflammed than noninflammed
tissue and were inversely correlated to the amount of
collagen in the tissue (696).
IL-1 has furthermore been demonstrated to function as a potent
inducer of MMP in fibroblasts, which induces
degradation of the ECM (637).
Furthermore, IL-1 has been shown to incude MMP activity and to diminish
collagen synthesis in cardiac fibroblasts and thereby contribute to
the remodeling of interstitial collagen in cardiac
muscle (597).
This is interesting, as mechanical loading results in IL-1 produced from fibroblast (590),
and more recently that chronic loading of
rabbit tendon resulted in rising levels of
mRNA for IL-1 (30).
It has been shown that mechanical loading of
human tendon cells release ATP and that this stimulates expression
of IL-1 (and MMPs) (634).
Furthermore, the IL-1 response is triggering COX-2, IL-6, MMP-1, and MMP-3
responses, a fact that could initiate tissue degradation and
remodeling in response to mechanical loading (635).
D. IGF and
IGF-Binding Proteins
IGF-I enhances collagen synthesis in equine flexor tendon in a
dose-dependent manner (468),
and it has been demonstrated that mechanical stimulation
of rat tendons by vibration results in
increased IGF-I immunoreactivity of
intratendinous fibroblasts (261).
From studies on flexor tendons of
rabbits it was shown that IGF-I administration was able to accelerate
the ECM protein synthesis, with some variation between segments
of tendons and between tendons from
various regions of the body (8,
10).
This is in accordance with a reduced functional deficit and an
acelerated recovery after experimentally induced tendon injury when
IGF-I was administered (360).
Finally, IGF-II was shown to be as potent a stimulator as IGF-I for
ECM turnover (7).
In cardiac fibroblasts, the combined effect of
mechanical loading and growth factors was studied. IGF-I was found to
enhance expression of procollagen type I by threefold
above that of mechanical stimulation alone (110).
Furthermore, a role for IGF-I has repeatedly been documented
for mediating the effect of
mechanical loading on bone surface cells preceding bone formation (392,
524).
In dwarf rats, the administration of
growth hormone and the subsequent increase in circulating levels
of IGF-I caused an increased expression
of both collagen type I and III in intramuscular
fibroblasts (684).
Together, these findings indicate that IGF-I is directly involved in
tendon and muscle ECM synthesis in relation to mechanical loading.
The fact that MMPs can stimulate IGF-binding proteins (BPs) to cause
a proteolysis of these substances provides a
possibility for a regulation of the
free IGF-I concentration in tissue and circulating blood which is
coupled to the the activity in the collagen degradation pathways (211).
IGF-BP-1 can be increased by IL-1, IL-6, or tumor necrosis factor- (565),
which in turn can regulate the bioactivity of
IGF-I. It has been shown that IGF-BP proteolysis occurs in response
to prolonged physical training in humans (555).
|
VIII.
COUPLING OF REGULATORY PATHWAYS FOR EXTRACELLULAR MATRIX TURNOVER AND SKELETAL MUSCLE CELLS TO
MECHANICAL TISSUE LOADING |
A.
Development of Skeletal Muscle and Intramuscular ECM
During muscle development it is clear that processes within the
cells of the ECM are required to ensure myoblast
migration, proliferation, and differentiation (39,
106,
448).
Fibronectin promotes myoblast adhesion and proliferation but inhibits
differentiation (210)
and participates together with decorin in collagen fibrillogenesis,
thereby providing the morphogenesis of the
intramuscular connective tissue. In contrast, laminin has been shown
to promote myoblast adhesion, proliferation, and myotube formation
(210,
352,
357a).
An important mediator of the
matrix cell interaction is integrin.
Interactions seen between myoblasts and ECM components such as
collagen type I, fibronectin, and laminin included integrins with
1-component, and blockade of
this inhibits differentiation of the
muscle cell (390,
391).
In addition, the cytoplasmic domain of the
-unit of integrin is involved in the interaction
between the muscle cell and its cytoskeletal proteins (556,
644,
645,
647).
Interestingly, in vitro studies have shown that when myoblasts are
grown on media with either fibril-forming type I collagen or type I
collagen without fibril formation, the former resulted in more
pseudopod formations and whenever these crossed collagen fibril focal
adhesion spots were localized by staining of
talin (390).
These findings indicate that collagen fibrils help with the
orientation and alignment of
muscle fibers. The exact role
of small leucine-rich PGs such as
fibromodulin, lumican, biglycan, and decorin for development
of the myocytes is not known, but it
could be that these substances stimulate growth factors such as
TGF-, myostatin, IGF, or hepatocyte growth factor. Overall, the
findings are indicative for a close coupling between myogenesis and
development of the intramuscular ECM components (86,
145,
578).
B.
ECM and Skeletal Muscle Interplay in Mature Tissue
The next question is whether adaptation to mechanical loading in
mature muscle and connective tissue involves a similar interplay as
in developing muscle (277,
278,
280).
Given that intramuscular connective tissue together with cytoskeletal
proteins represents a vital structure in the force transmission from
contractile elements in the muscle fiber to the resultant movement
of a joint, it would make sense if
these processes were somewhat interconnected. It is known that
intense physical activity like repeated eccentric contraction is
associated with ultrastructural muscle damage like Z-line streaming,
overextended sarcomeres, disorganization of
myofilaments, and t-tubule damage of
the skeletal muscle tissue in both animals and humans (103,
104,
218,
219a,
400,
402,
405,
406).
Additionally, there is a release of
creatine kinase from the muscle, as well as a fall in active tension
and a rise in passive tension (26,
517).
In line with this, the destruction of the
cytoskeletal structures is seen early as well as immediately after
intense electrically induced muscle contractions (406),
which is subsequently followed by inflammation and regeneration
processes (26,
517).
Whereas animal studies in general demonstrate quite marked changes in
myofibrillar and cytoskeletal protein
damage (55,
406),
human data often fail to show any major
myofibrillar changes or cytoskeletal
damage (149,
704).
Instead, human data demonstrate inflammatory changes such as positive
staining for cytokines and histological demonstration of
inflammatory cell infiltration and tissue disruption in the
intramuscular connective tissue of the
endo- and perimysium, with a surprisingly intact picture
of the cytoskeletal proteins (149,
704).
As earlier mentioned, an altered loading pattern in animal
musculature results in changes in intramuscular collagen formation
and degradation (569,
570),
and intense eccentric muscular exercise in rats will increase the
enzymatic activity of the
MMPs and its TIMPs responsible for the degradation of especially collagen type IV in
skeletal muscle (346).
Also in human skeletal muscle, it has been demonstrated that
chronic electrical stimulation over longer periods increases the
MMP activity, together with no major change of
collagen type IV content in muscle (342).
It has been found that MMP-2 and -9 expression is upregulated with
experimentally injured skeletal muscle and in mice with lack
of dystrophin, in the way that MMP-9
increased for a prolonged period related to inflammation, whereas
MMP-2 was correlated with formation of new
myofibers (328).
Furthermore, it has been shown that the concentration of
procollagen propeptides in endomysial and perimysial connective
tissue increases, indicating increased collagen turnover (149).
Attempts to study simultaneously the response of
protein synthesis in both myofibers and fibroblasts to exercise have
recently been performed (452).
Findings in human thigh muscle indicate that the extent and time
course of change in protein synthesis support
the view that myofibers and fibroblasts receive input
from common signaling pathways, which are responsible for the
conversion of mechanical loading into anabolic stimuli (452).
One way to view any potential cross-talk between loading, intramuscular
connective tissue, and skeletal muscle adaptation is to investigate
myogenic stem cells such as satellite cell activation. It has
been suggested that disruption of the
cytoskeletal proteins and thus the cellular integrity of the
myofiber triggers the release
of appropriate growth factors from within the
myofiber (284,
402,
416,
449),
and in some animal models the time pattern of
such changes is compatible with this hypothesis. Satellite cell
activation (147,
157)
normally is associated with myofiber damage and disruption
of the sarcolemma (649),
but in vitro studies (26)
and human experiments, where variation in training activity was
studied either in a cross-sectional or longitudinal design (310,
311),
have documented activation of
satellite cells in response to chronic exercise as evidenced by
positive staining with neural cell adhesion molecule (N-CAM).
Detection of fetal antigen 1 (FA1) has recently
been shown to determine activition of
myogenic stem cells (205,
302),
and both the staining for FA1 (and N-CAM) located between the basal
lamina and the sarcolemma and the detectable interstitial
concentration of FA1 in heavily exercised muscle were
found to increase in humans for at least 8 days after vigorous
one-legged eccentric contraction (149).
Despite microdialysis and biopsy sampling, no changes in FA1
were seen in the contralateral resting control leg. Accompanying
these responses were marked rises in circulating creatine kinase
(up to 50,000 IU/ml), pronounced clinical symptoms, and absence
of any light-microscopic changes in desmin,
dystrophin, or fibronectin proteins. However, activation
of satellite cells was accompanied by
increased staining for PINP as well as for tenacin C (149).
Whereas PINP indicates collagen type I synthesis in the ECM
which is known to be coupled to degree of
loading, tenascin C is controlled by tensile stress and is regulated
at the transcriptional level via stretch-responsive cis-acting
regions in the promotor gene (207)
and reinforces the lateral adhesion of the
myofiber to the surrounding endomysium.
From these observations it may be hypothesized that during intense
muscle loading in humans shear stresses associated with axial force
production intramuscularly influences the inhomogeneous ECM network
either by inducing a microtear or by signaling to existing
fibroblasts to release growth factors that subsequently will initiate
an activation of the
quiescent satellite cells (446),
or by initiating the direct release of
growth factors from within the myofiber. In either of
these situations, it may be hypothesized that turnover rates for
intramuscular connective tissue are not necessarily identical for
tendon and muscle, but that ECM turnover in muscle is coupled more to
turnover of skeletal muscle such as myofibrillar proteins.
It also remains clear that satellite cell activation can be
initiated in the absence of
gross disruption to cytoskeletal proteins (522).
This does not exclude a role
of changes in cytoskeletal proteins for
stimulation of muscle contractile protein synthesis.
Interestingly, eccentric loading in rat musculature has been
shown to result in loss of
desmin immunostaining immediately after loading, but followed by a
marked increase in desmin above basal levels (55).
This could suggest that the intermediate filament system
of the muscle may in fact adapt favorably to
eccentric loading and become more resistant to subsequent loading,
which together with adaptation in the connective tissue could
explain the much less damaging effect on muscle to subsequent
bout of eccentric exercise (517).
However, curiously, the same author group showed that desmin knockout
mice were less likely to get injury than control ones (564).
Still, it remains clear that the adaptive responses of
cytoskeletal proteins and ECM components most likely play in concert
when subjected to mechanical loading. This can be shown during
regeneration processes, where it is clear that expression and
formation of dystrophin, integrin as well as
other subsarcolemmal, and transmembrane proteins play an important
role in the internal linking of the
cytoskeleton to the plasma membrane before a linkage of the
myofibers to the ECM occurs (315,
320, 643).
The mechanism behind a potential signaling between the ECM and
myofibrillar components is unknown in relation to
mechanical loading. It can be hypothesized that stores of ECM
growth factors are released upon mechanical loading (649).
In line with this, PGs (e.g., decorin) are demonstrated to bind
growth factors and control flux of
growth factors to and from the ECM (646,
647).
Among the proposed growth factors are hepatocytic growth factor
(HGF), IGF-I, IL-6, IL-15, insulin, leptin, FGF, leukemia inhibitory
factor (LIF), and testosterone. The fact that inflammatory cells
infiltrate regions subjected to heavy loading provides the
possibility that release of
cytokines plays a central role. However, HGF found in noninjured
muscle (621)
is also a strong candidate.
The reason for the dissociation in localization of
damage and tissue reaction between models used in different species
(e.g., voluntary activity in human muscle versus electrical
induced muscle lengthening in animals) could be due to the degree
of motor unit synchronization and thus
muscle cell activity coordination during the eccentric activity. As
indicated on Figure
9, voluntary eccentric exercise results in high force output, but
somewhat low and unsynchronized activity pattern as judged from EMG
recorded motor unit synchronization (189,
588).
Interestingly, EMG activity increased and motor unit recruitment
became more coordinated in trained individuals (1).
This implies that individuals who are subjected to unaccustomed
eccentric contraction display an unccordinated motor unit activation
pattern, an thus place a high stress on intramuscular ECM between
muscle fibers that are contracting and those that are relaxed. In
contrast to this, electrical stimulation will tend to activate all
available muscle fibers irrespective of
type and motor unit origin (189).
In the latter case, shear stress between fibers will be less
than in the former situation, and if tensile strength is
sufficiently high it may cause damage within the muscle cell itself
rater than in the ECM. Although it remains to be proven, there
is reason to believe that ECM plays a greater role
in muscle adaptation to voluntary exercise in humans than previously
thought, and thus contributes to mechanosensing and to ensure
adaptation of connective tissue and skeletal muscle that is
coordinated to have the greatest possible functional ability.
 649 -- Physiological Reviews_files/z9j0020403060009.gif)
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|
FIG. 9. Intense
loading of skeletal muscle and adaptive
responses in extracellular matrix. Hypothetical interaction
between extracellular matrix, cytoskeletal proteins, and
skeletal muscle fibers in response to eccentric loading
of the contracting musculature,
whether or not they are trained or untrained.
| |
|
IX.
CLINICAL PERSPECTIVES: PHYSIOLOGICAL UNDERSTANDING OF TISSUE OVERUSE
|
Overloading
and prolonged overuse of musculotendinous structures leads to
tissue maladaptation and damage and to clinical symptoms. Within
tendon structures the development of
chronic pain associated with subsequent loading in regions
of, e.g., the Achilles, patellar, and
supraspinatus tendons, remains a major etiological, pathophysiological,
and treatment challenge (66,
80,
92,
122,
141,
216,
232,
235,
236,
240,
308,
309,
340,
467,
514,
527,
546,
609,
688).
In muscle, the delayed-onset muscle soreness, after eccentric
loading, as well as muscle-associated chronic pain associated with
long-term overuse has been the focus for intense investigations but
still demands better pathophysiological explanations (281,
517).
A. Tendon
Overuse
Repetitive loading of human tendon tissue often
leads to overuse injury that result in severe clinical symptomatology
including pain, regional swelling, and soreness elicited either in
relation to occupational procedures or to sporting activity in
elite athletes and recreational exercisers (305,
332,
351,
362–365,
472).
Although the term overuse refers to the fact that repetitive
loading has elicited the symptoms and suggests that the physical
load exerted on the tissue is important for the etiology of this clinical problem (585),
only limited knowledge is available regarding the pathophysiological
reactions in the ECM in such conditions. This explains part
of the difficulty encompassing all
tendon-related injuries under one entity (299,
316).
It becomes however clear from the present literature that some
of the overuse injuries are associated with
changes within the tendon substance itself due to either a primary
alteration in the biochemical composition (307)
to a preceding mechanical elicited partial rupture (4,
34,
364,
366), or to gradually developing degenerative changes (5,
299).
Furthermore, some injuries occur along the tendon, often
in relation to the tendon sheet or in the peritendinous region
containing loose connective tissue and vessels, and these injuries
are often due to the travel of
tendon over bony or cartilage structure (62).
Finally, other tendon-related overuse injuries are related to the
insertion of the tendon upon bony structure (61).
With regard to the pathophysiology of
injury development, three major points deserve further discussion.
The first is the presence and potential importance of
inflammatory reactions with overuse injuries, the second is
regulation of blood flow and tissue metabolism in
over-used connective tissue, and the third is how pain is originated
and mediated in situations with overused tendons or muscle.
B.
Development of Tendon Injury: Predisposing Factors
Predisposing factors influence the frequency of
tendon overload symptoms and ruptures. As examples, both genetic (59,
596),
blood type (306,
358),
accompanying presence of chronic disease (316),
and drug use (285,
542)
have been demonstrated to be significant predisposing factors. The
genetic role remains to be elucidated, but
heritage and twin studies have shown a definitive role
(59,
596).
With regard to influence of
drugs, especially the use of
fluoroquinolones has been found, at least in high doses, to cause an
increased activation of MMP activity, which provides a basis
for an accelerated degradation rate of
tissue collagen (679).
Factors such as high body weight, leg length inequality, foot
abnormalities (such as pes cavus or planus), and low joint, tendon,
or muscle flexibility are identified as moderately important factors
for development of tendon injury, but the evidence is
mainly based on associations rather than any demonstration
of a cause- and-effect relationship (366).
A potential damaging effect on the tendon tissue has been proposed
to be elicited by changes in tissue temperature in relation to
muscular activity. In equine flexor tendons, it has been shown that
gallop exercise elevated the intratendinous temperature by 5–6°C,
which is sufficient to theoretically account for some detrimental
effect to fibroblast activity. Fibroblasts cultured from the core
of the equine superficial digital flexor
tendon were subjected to temperatures up to 45°C, and cell
survival fraction was determined and compared with control dermal
fibroblasts and kidney fibroblasts (72,
75).
It was shown that no major tendon cell death occurred by subjecting
cells for shorter periods to the physiological temperature increases
observed in core tendon tissue found during exercise (75).
When the temperature was increased to supraphysiological 46–48°C, a
marked cell death was observed (75).
These findings cannot directly be transferred to humans in whom
longer periods of exposure to tendon loading are
often seen. Furthermore, the in vitro
experimental setup in the equine fibroblast cultures was done
with cells under suspension, which is known to increase their
resistance to heating (600).
Dramatic temperature increases have previously been shown to alter
the viscoelastic properties of
tendons (671)
and passive structures in skeletal muscle (560)
to, at least theoretically, allow for a wider range of
motion in the joints and increased extensibility of the
tendons. Interestingly, the physiological changes in temperature that
occur intramuscularly during exercise in humans do not result in any
changes in the muscle-tendon viscoelastic properties when determined
in vivo (423).
Therefore, at this point, it is unlikely that temperature changes
observed during exercise will result in any altered extensibility in
tendon or muscle, and it is doubtful whether temperature changes are
of any major importance for tendon pathology
in relation to exercise.
C.
Tendon Rupture: Preceding Overuse
The above-described predisposing factors, to a very minor degree,
offer mechanistic explanation for the development
of tendon injury. However, studies on
overloaded tissue have provided some suggestion as to the reason for
tissue overload. In individuals who are subjected to an Achilles
tendon rupture it has been found that there is a degenerative region
of the tendon that preceded the loading
that elicited rupture (5,
316,
622).
With a chronic overload injury to a tendon, recent data have
indicated an upregulation in both type I and III collagen expression
and content with a preference for the latter, and thus a
decrease of the type I to type III ratio (294).
This fits with observations on ruptured tendon, where the amount
of type III was elevated and the ratio
between type I and III was lowered at the ruptured site compared with
intact cadaver tendons in both humans and equines (72,
139,
146,
307).
It has furthermore been shown that cultured fibroblasts from ruptured
Achilles tendon produce more type III collagen than fibroblasts from
normal tendon (420).
Even stronger proof for a local upregulation of
type III collagen was found in a study where tendon tissue at the
ruptured site contained more type III collagen compared with both
cadavers and to more distal sites within the ruptured tendon itself
(191).
In addition to an upregulation of
collagen type III in healing tendon, the amount of
fibronectin also rose (677).
A determination of
procollagen propeptides and collagen fragments revealed that apart
from a decrease in the amount of
PINP, and thus a reduced collagen type I synthesis, at the ruptured
site, no alterations for indicators of
collagen type II synthesis or degradation were found (191).
This indicates that the rise in type III collagen is occurring slowly
and that the process responsible for collagen type III accumulation
at the ruptured site occurs far before the actual rupturing trauma.
Type III collagen fibrils are thinner than type I fibrils (563),
and interestingly, the finding of increased amount of
type III collagen in ruptured areas of
tendon fits with the observations of
Magnusson et al. (431)
who found that there was a site-specific relative loss of
larger fibrils and thus a relative increase in smaller diameter
fibrils both at the deep and the superficial part at the tendon
rupture site.
Also in accordance with the biochemical examinations, the fibril
size was normal in the more proximal and healthy-looking parts
of the ruptured tendon (431).
This implies first of all that changes in type III
collagen content and in fibril diameter are site specific within the
tendon, and furthermore, it suggests that there is biochemical and
structural support for a regional decrease in tendon resistance to
loading. In horses, the occurrence of
small-diameter fibrils has been observed in the core of
tendons subjected to long-term intense exercise, which has been
suggested to be a result of
disassembly of fibrils or a splitting of
existing larger fibrils (601).
From the available human data it is a result of a
gradually altered content of the
fibrils from type I to type III fibrils. It has been described that
healing tendons have fibril populations of
smaller diameter than in healthy tendons (441),
and it is likely that small mechanical damages result in local
healing of tendon tissue with increased amount
of type III collagen, which with continuous
training can be exchanged to type I collagen-dominated fibrils. It is
interesting that in patients with prolonged pain and signs
of unilateral tendinopathy, training
increased their collagen type I synthesis compared with the
contralateral healthy tendon and moreover improved their overall
symptoms by completing a prolonged training protocol with loading
of the tendon (M. Kjær, C. Clement, N.
Risum, and H. Langberg, unpublished observations). From this it can
be suggested that training a reasonable amount increases the collagen
type I to III ratio in tendon with chronic overuse and will thus
counteract the vulnerability toward acute tendon ruptures. Such a
view would also be compatible with the demonstration of a
gradual change in collagen expression of
individual fibrils, as hybrids of
these have been demonstrated (203).
Another important finding in patients with chronic Achilles tendon
disorder is the demonstration of
lower levels of MMP-3 mRNA, which indicates that ECM
degradation and tissue remodeling is impaired in this situation (294).
This finding is in agreement with the demonstration of the
side effect of tendon pain and problems, when using
MMP inhibitor as experimental drugs in cancer treatment trials (171).
Interestingly, decreased expression of MMP
in chronic tendon problems is in contrast to the documented rise in
MMP-2 and TIMP-1 and -2 expression and activation in rabbit
supraspinatus tendons undergoing a healing process after surgical
rupture (131).
D.
Experimental Tendon-Overuse Models
Several animal exercise models have tried to create overload
of tendons. Such models would allow for evaluation
at early stages of
tissue overloading. Dogs and rabbits have been used to stimulate
degenerative and inflammatory changes in tendon with the use
of different types of
electrical muscle stimulation and ergometer devices (31,
45,
46,
92).
With these models it has been possible to demonstrate thickening and
infiltration of
inflammatory cells in the tendon, increased number of
capillaries both within and around the tendon, and fibrosis in the
paratenon after intense eccentric loading in young, developing
rabbits (45,
46).
Somewhat in contrast, a more moderate, but also more physiological
relevant, stimulation regimen in adult rabbits over several weeks did
not result in any inflammatory or degenerative changes within or
around the loaded Achilles tendon (31).
In the rat, experimental designs to study tendon rupture and
muscle injury have been performed (33,
56),
but it has been somewhat more problematic to create a model that
mimics the chronic overuse disorder that occurs in humans. In one
attempt, Messner et al. (450)
subjected rats to repetitive electrical-induced eccentric exercise in
a kicking machine and found that only around one-half of the
animals achieved histological changes in and around the tendon. This
occurred despite using a protocol that previously was used to induce
muscle damage in rats (455).
Furthermore, the changes were discrete and more of a
proliferative and reparative nature than they were directly
degenerative (450).
Hypervascularization and increase of
neural elements were mainly observed in epi- and peritendinous tissue
(450).
Taken together, small animal models only to a limited degree provides
inflammatory or degenerative changes. Furthermore, in the cases where
overuse histological changes are demonstrated, it occurred after
extremely intense artificial and supraphysiological stimulation. When
exercised voluntarily it seems far more difficult to create an
animal tendon (or intramuscular connective tissue) overuse model.
In the horse, the occurrence of
tendon-overuse injuries seem more similar to those of
humans, and overuse signs in the flexor tendons resembles, to some
extent, that of the Achilles tendon disorder in
humans (72).
The fact is that only horses and greyhound dogs (502),
which are undergoing forced regimens of
exercise, display overuse injuries similar to those in humans,
whereas other animals only display tendon overuse when extreme and
unphysiological regimens are imposed. Therefore, there is a puzzling
problem of why human tendons are so prone to overuse, and
why no signaling mechanism is provided for the human to avoid
training into overuse problems.
E.
Tendon Overuse and Inflammation
Lack of identification of
inflammatory cells in tissue samples from tendons with overuse
symptoms (307)
has contributed to a skeptical attitude towards the concept
of overuse-related inflammation and
caused the general injury terminology to be changed from -itis to
-osis and -pathy. This is supported by finding of
perioperative intratendinous degeneration including increased amounts
of noncollagenous matrix, focal variation in cellular
content, and vascularization as well as alterations in the structure
and arrangement of collagen fibrils in tendons from
individuals with long-term clinical tendon problems (4–6,
34,
299,
306,
462–464).
Hyaline, mucoid, and fibrinoid degeneration as well as calcification
and formation of fibrocartilago have been observed
with electron microscopy (61,
62,
307).
However, it has been difficult to completely exclude an
inflammatory component in tendon overuse injury, and clinical
observations of
swelling, pain, and warming along the diseased tendon in relation to
acute loading episodes of an overused tendon (25)
as well as the proven positive effect of
anti-inflammatory medication aiming at an inhibition of the
prostaglandin synthesis by blocking cyclooxygenase or by using
corticosteroids (216)
support this doubt.
The possibilities for monitoring the degree of
inflammation within the relevant tissue have so far been limited.
More recently, this question has been addressed by determination
of tissue concentrations of
prostaglandin intratendinously in both the human Achilles and
patellar tendon as well as in the lateral elbow with microdialysis,
in which no elevated level of
PGE has been found in any of the
regions during rest (18–20,
23).
This is in contrast to determinations of
homogenized tendon tissue as well as in fibroblast cultures grown
from human tendons in which a detectable concentration level and
expression of prostaglandin were demonstrated, and
where levels were higher in overused tendons compared with healthy
counterparts (223).
This was accompanied by an overexpression of
PDGF receptor (PDGFR-) (551)
and an elevated expression and production of
active TGF-1 (223).
This suggests an altered expression and synthesis of growth factors and inflammatory
mediators in fibroblasts from overused tendons. No investigation
of inflammatory markers within tendons
has been conducted during exercise, but data on peritendinous
measurements indicate that in the injured tendon region during
exercise prostaglandin levels were significantly higher around
the Achilles tendon of an
individual that was overuse injured compared with the contralateral
healthy tendon (376).
This could imply that the injured tendon represents a vulnerable
structure that due to adhesions in the peritendon region (9)
more easily displays inflammatory reactions upon loading. Whether
such a rise in inflammation plays an important stimulating or
detrimental effect in the regeneration or on nociceptive processes
has not been widely addressed (466,
709).
It has been shown that nonsteroidal anti-inflammatory drugs
(NSAIDs) in the form of
aspirin, phenylbutazone, or indomethacin increased the strength
of various uninjured collagen structures
in rats, which is potentially related to an increased collagen
cross-linking (659).
Furthermore, the cyclooxygenase unspecific NSAID piroxicam increased
the strength of healing rat ligaments, but did not
influence the ultimate strength once the the healing was complete,
nor did it affect uninjured ligaments (154).
Somewhat in contrast, recent studies on cycloxygenase specific
(COX-2) inhibitors (celecoxib) indicate that a small reduction in
ligament strength occurred during early healing (186).
In that study no long-term results were provided, and COX-2
inhibition did not affect the intact ligaments of the
animals (186).
Whether blockade of
arachidonic pathways to limit inflammation has any effect on
regeneration or healing processes in overloaded tendons in vivo is
currently unknown. It is interesting that a recent study documented
tissue damage and thereby detrimental effect of
prostaglandin administration to animal tendon tissue (611).
F.
Tendon Overuse, Blood Flow, and Tissue Oxygenation
The fact that the most frequent location of
painful Achilles tendon condition coincides with the area with the
most anatomically limited vasculature has led to the suggestion that
impaired supply of
vasculature and thus insufficient blood flow under loading conditions
could lead to tendon degeneration (188,
266).
It has been found that degenerated shoulder tendons in humans
have a reduced capillary density (67).
Interestingly, physical training in hypobaric hypoxic environment
resulted in selectively increased collagen type III and IV expression
in rat heart ventricular muscle, whereas type I collagen was
unchanged (507).
It is not known whether the same pattern is present in tendon, but
it would fit with hypoxia favoring degenerative changes and a
predominance of
type III collagen, and thus a reduction in ultimate tensile tendon
strength. Furthermore, ischemia in the brain has been shown to result
in release of MMP-9 to the extracellular tissue (511),
and that it influences the magnitude of
postischemia infarction. This is so, as pharmacological blockade
of MMP-9 is found to decrease infarct
volume and to prevent the oxidative stress-associated blood-brain
barrier disruption (230,
552).
A similar effect is seen in MMP-9 knock-out mice (38).
In relation to experimental spinal cord lesions it has furthermore
been suggested that the increased MMP-2 and -9 response is
beneficial in tissue remodeling and that it can be used
therapeutically (175).
Likewise, in hindlimb muscle vasculature, MMP activation is important
for an initiation of ischemia-induced angiogenesis
through VEGF (594).
During pharmacologically induced vasodilation in rat skeletal muscle,
MMP-9 is increased, and the presence of
MMP-2 and MT1-MMP are important for initiation of the
training induced angiogenesis in skeletal muscle (251,
252).
Potentially this effect is mediated through collagen-derived
proteolytic fragments (438).
It can therefore be hypothesized that ischemia in tendon or muscle
can initiate processes of collagen degradation.
A higher lactate concentration in the interstitial fluid of human tendon was demonstrated using
microdialysis in patients with painful chronic tendinosis compared
with healthy pain-free tendons (17).
This could indicate a higher anaerobic metabolism in overused
tendons, which is a phenomenon that could be related to a more dense
ECM area of degeneration in the core of
the tendon, that would lead to a compensatory neovascularization
in other regions, similar to that found in the ventral part
of the Achilles tendon (489a).
Speaking against hypoxia of
the tendon as a contributing factor for the development of
overuse injury is the fact that no demonstrable ischemia could be
found intratendinously even with intense loading of
healthy tendon tissue (93,
94).
It should however be kept in mind that the human tendon can be very
heterogeneous along its length with regard to vascularization and
morphology. It has been shown in the Achilles tendon that the distal
and the proximal part has the highest vascular density, and the
lowest was found in the middle part of the
tendon (705).
Likewise, the CSA of the human Achilles tendon was
thickest in the distal part and thinnest in the proximal part (430).
The combination of variable CSA and vascularity along
the tendon length can indicate that adaptability towards training
of the tendon is also region specific (430).
Interestingly, the difference in tendon CSA between athletes
and sedentary individuals was most pronounced in the distal
part of the tendon, which supports the idea
of a region-specific hypertrophy in
response to habitual running, and furthermore can provide the basis
for identifying tendon regions that are vulnerable towards injury
development (430).
G. Tendon Injury
and Pain
Overused tendons are shown to possess increased levels of
glutamate when investigated in the resting state using microdialysis
in Achilles and patellar tendons (18,
23).
Furthermore, immunohistochemical analysis of
tendon biopsies revealed the presence of
ionotrophic glutamate receptor N-methyl-D-aspartate (NMDA) in relation to nerves (18,
19).
The exact role of
these responses is not clear, but the excitatory neurotransmittor
glutamate is known to be a potent pain modulator in human central
nervous system, and glutamate is thus a candidate for causing pain
with overuse in tendons. Furthermore, its nociceptive role
is known to be additive with that of
substance P (8),
a substance that has been demonstrated in the peritendinous region
of both rats (450)
and rabbits (8).
In animals, experimental damage to the Achilles tendon has been shown
to introduce vascular and nervous tissue into the tendon itself, and
thus increase the content of
substance P (8).
It should be emphasized that in intact tendons without partial
rupture, no sign of substance P has been demonstrated
within the tendon.
In addition to these findings, mechanical loading is also found to
elicit increased interstitial concentrations of the
nociceptive agent bradykinin in the peritendinous tissue
of human tendon (375),
which further adds to the hypothesis that alterations in the levels
of several nociceptive agents act in concert
to elicit overuse injury-related pain symptoms originated
primarily peritendinously. In association with the release
of substance P, CGRP has also been
demonstrated in animals (8,
450).
Levels of this substance have been found to be related to
the vasculature and to be relatively higher in tendon compared with
both ligament and the joint capsule (8).
Furthermore, increased tissue levels of
CGRP were associated with mechanical tissue damage due to overloading
in animal tendon (8).
Whether this is the case in humans is not known, but it could
contribute to explain the tendon hyperemia and hyperperfusion that is
found in human overloaded tendons (6).
Together with CGRP, also prostaglandin and prostacyclins could also
contribute to hypervascularization in overused tendons.
Interestingly, the exercise-induced rise in tissue prostaglandin
can be blocked by cyclooxygenase blocking agents, and it has
been shown that the peritendinous blood flow increase is inhibited
by 40% when prostaglandin synthesis was blocked (96).
H.
Perspectives for Treatment
Treatment of tendon-overuse injuries and painful muscle
conditions are still widely debated due to lack of
full understanding of the underlying processes. With
regard to chronic tendon problems (tendinopathy), several
conservative treatments such as immobilization, physical therapy,
stretching, and pharmacological treatment with NSAIDs as well as
surgical procedures have by no means produced impressive results (307,
420).
Somewhat surprising, the use of
heavy resistance exercise has been shown to improve symptoms in these
patients. It was shown that resistance exercise had a positive effect
on symptoms in patients with prolonged tendon pain and that eccentric
training was superior to concentric exercise (421,
482)
and that significant results were obtained in patiens with long-term
Achilles tendinopathy awaiting surgical intervention undergoing a
12-wk training program (22).
Furthermore, long-term results support a lasting effect of
this intervention type (592).
The mechanism behind the effect of
adding load to a chronic overloaded and painful condition in unclear,
and resting intratendinous levels of
glutamate determined by microdialysis in human Achilles tendinosis
are not changed in response to such a 12-wk training program (21).
It might be that the loading of a
certain magnitude together with stretching the relevant structure
induces increased reorganization of the
collagen structures, which resulted in new synthesis of
especially type I collagen. In line with this, recent experiments in
elite athletes who had unilateral Achilles tendon pain and signs
of tendinopathy, the performance
of a 12-wk eccentric training program with
daily exercise added to their normal activity pattern, resulted
in an increase in collagen type I synthesis in the injured
tendon, whereas no change was observed in the contralateral
uninjured tendon that was not trained (H. Ellingsgaard, J. Jensen,
T. Madsen, H. Langberg, and M. Kjær, unpublished observations).
|
X.
FUTURE PERSPECTIVES |
Inhibition
of MMP activity has been used in clinical
trials with the aim to counteract cancer growth (84,
105,
313a).
MMP activation potentially involved in the apoptosis processes
by being a function of p53
gene expression increase in premature rupture of
fetal membranes (209).
However, despite the intuitive potential effects that such drugs
should have on counteracting degradation of
basement mebranes and limiting tumor invasion and metastasis, neither
the use of unspecific (192)
or more specific MMP inhibitors (60,
65)
has so far been proven very successful. One of the
reasons for this is that the role
of MMP in cancer is far more complex
than hitherto thought and involves angiogenesis in healthy tissue,
its production in fibroblasts and inflammatory cells in tissue
surrounding the tumor, as well as its autocrine action controlling
cell growth, death, and migration (148,
713).
MMP might play a pivotal role
in regenerative processes. This is supported by the finding
of an enhanced healing and reduced
number of anastomose leakages after colon surgery
when MMP inhibitors are given to patients, whereas MMP blockade
delayed healing of cutaneous wounds (2,
3).
It therefore seems challenging to enlighten the role
of MMP (and TIMPs) in relation to
mechanical loading and differentiate its role
in physiological perturbations of the
steady state of the fibroblast and the ECM, from its
role in pathological processes like healing
after tendon or muscle injury. It can be suggested that
collagen-degrading enzymes like MMP and their activity is one
of the key points in the tissue
adaptability to loading and training. This is at least compatible
with the finding that MMP inhibitors used in clinical trials reveal
musculoskeletal symptoms as their most prominent side effect (148,
274,
276).
Tendinitis, myalgia, and arthralgia are especially seen often,
despite change in the activity level of the
studied patients. It can therefore be hypothesized that high MMP
activity is a prerequisite for rapid adaptation to chronic loading
of tendon and muscle and that stimuli
that surpass this capacity in any amount will result in suboptimal
tissue adaptation and thus result in chronic symptoms. The tight
coupling of MMP activity and collagen deposition is
supported by observations in cardiac muscle, where MMP and their
regulators are crucial in remodeling after myocardial infarction
(150,
155)
and for development of myocardial fibrosis in heart
failure, and that this may be modified by MMP modulating drugs
(399,
606).
Furthermore, IL-1 and TNF- decrease collagen synthesis and activate MMPs 2, 9, and 13
(597).
The dimensions and architecture of a
tendon influence adaptive collagen responses to mechanical loading.
It is known that the tendon microstructure along the length
of the tendon reflects differences in
mechanical loading either due to external synovial tension (9)
or direct compression against bony structures (61,
548),
but its unknown to what extent intratendinous gliding (e.g., due to
endotenon disruption) contributes to pathological responses to
loading during differential muscle activity. Such phenomenon can also
play a role under circumstances where the
tendon is loaded differentially by activity from different muscle
groups (such as the triceps surae, when gastrocnemius is fatigued
earlier than soleus) under fatigue. Within muscle it can be
hypothesized that in situations with unaccustomed exercise patterns
such as eccentric loading, unequal motor unit activation results
in shear stress of the intramuscular connective tissue and
"spares" the cytoskeletal structures and the myofiber. In contrast, under
circumstances where all muscle fibers are contracted in a coordinated
fashion, such as under electrical stimulation with forced lengthening
or eccentric activity in individuals who have high experience
in eccentric loading (weight lifters, etc.), the damage on the
muscle occurs in cytoskeletal structures and thus results in
less pain (Fig.
9). In addition to this, it is unknown what relative
role the different collagen types play in tissue
adaptation to chronic loading (133).
Preliminary investigations have been performed in humans with
collagen defects (430)
or with inflammatory muscle diseases (353),
but a more systematic investigation of the role
of exercise for tissue adaptive responses in
diseases that interfere with the ECM is not known. In that respect,
the ability of relatively noninvasive imaging techniques will
allow for better and more mechanistic insightful investigations
in the future (608,
712).
The intramuscular amount of ECM
can most likely increase with physical training (350,
507),
an interesting phenomenon since the beneficial importance
of passive structures in contracting
muscle with regard for force production has recently been stressed
(273,
680,
681). The balance between the presence of
contractile elements and extracellular force transmitting
energy-enhancing matrix
is yet to be established, but points so far at a more intimate
interplay for optimal function of
skeletal muscle. It is interesting to note that during remodeling
of muscle tissue, ECM substances can to
some extent substitute for each other, e.g., agrin can substitute for
dystrophin (457).
This opens a possibility not only for understanding redundant
phenomenon in ECM adaptation to mechanical loading, but opens wide
perspectives with regard to interference into diseases that involve
ECM or cytoskeletal errors.
The influence of chronic mechanical stretching of ECM
in tendon and muscle deserves further observations. With the use
of new visualization modalities like in
situ X-ray defraction, it has been possible to demonstrate that the
overall strain of a tendon surpasses that
of the individual fibrils, and it is proposed
that major movement between fibrils takes place (523).
This suggests that fibrils and interfibrillar matrix
form a coupled viscoelastic system. Furthermore, with the use
of confocal laser microscopy, it has
recently been possible to demonstrate the mechanical deformation
of tendon fibroblast during loading, a
phenomenon that may very well explain magnitude of
responses in the mechanical signal transduction pathway of ECM
in tendon and muscle (35).
Finally, the mechanism behind unilateral increased flexibility after
chronic stretching exercises, despite unaltered passive viscoelastic
properties of the muscle tendon unit (434),
calls upon investigating peripheral feedback mechanism from
relevant receptors in muscle and tendon, and its potential interplay
with central pathways involved in stretch perception. Until
these mechanisms are described in detail, we only know that
stretching will improve flexibility, but we have no support to
use flexibility training as a preventive measure for acute or chronic
sports injury development due to altered passive mechanical
properties of the tissue.
The fact that data tend to support an adaptive mechanism in ECM to
loading that includes both structural and functional adaptations with
a potential of incresasing the resistance toward
tissue fatigue and rupture raises the ultimate question of
how this adaptation takes place (575).
Is the ECM, and collagen especially, subjected to repeated
microtrauma resulting in tissue damage and subsequent repair
processes (324,
470,
593),
or is it driven by biochemical and physiological processes that
are governed by an exercise-induced increase in protein
degradation followed by a stimulation of
protein synthesis of relevant substances (540).
Neither of the two mechanisms exclude each other, but
it is hypothesized that whereas the former mainly takes place
when tendon and muscle are subjected to high sudden loads at
the loading limit of the
structure and causing tertiary creep, the latter is the most common
event occurring in relation to repeated loading where the recovery
time is too short to allow for a physiological adaptation. This also
suggests that overuse injury of
connective tissue is a mismatch between synthesizing and degrading
biochemical pathways. Clearly, in addition to investigating
loading-associated tissue adaptations, findings would have to be
related to the possibility that certain collagen gene expressions are
more likely to adapt to altered loading than others (144).
We are only at the beginning of
understanding the factors eliciting synthesis of
collagen and other structural proteins of the
ECM in tendon and skeletal muscle in response to mechanical
loading. In vitro experiments are gradually being supported by in
vivo human experiments [e.g., by use of
microdialysis (685),
stable isotopes, and various imaging techniques] that allow for a
determination of the
time pattern of responses to exercise and of the
correlation between growth factors and collagen synthesis (44).
However, such studies in no way prove that a causal relationship
exists between phenomenon, and future studies using
administration of
potential regulatory factors either administered systemically or
locally into the tissue in physiological concentrations are needed to
understand the acute tissue growth regulation of
ECM of tendon and muscle. This needs to be performed
both in the resting state as well as during exercise. Furthermore, to
differentiate the adaptation of the
tissue to prolonged loading, the development of
overuse models in humans will be crucial. Only in this way will it be
possible to define and study the borderline between the optimal
physiological adaptation with strengthening of
tendon as well as ECM in skeletal muscle, and its maladaptation
that ultimately leads to tissue changes and symptoms that are
associated with an overuse injury. The in vivo models, in combination
with modern molecular techniques, can help us not only achieve
mechanistic insight, but will also in a physiological sense provide
us with tools to integrate the understanding of
these processes and most importantly to place the different molecular
processes into a hierarchy of
tissue responses to mechanical loading. This will be a prerequisite
to improve treatment regimens and evaluate pharmacologial
intervention in tissue overloading (40).
|
XI.
SUMMARY |
The ECM,
and especially the connective tissue with its collagen, links tissues
of the body together and plays an important
role in the force transmission and
tissue structure maintenance especially in tendons, ligaments, bone,
and muscle. The ECM turnover is influenced by physical activity, and
both collagen synthesis as well as activity of
degrading metalloprotease enzymes increase with mechanical loading.
Both transcription and posttranslational modifications, as well as
local and systemic release of
growth factors, are enhanced following exercise. For tendons,
metabolic activity, circulatory responses, and collagen turnover are
demonstrated to be more pronounced in humans that hitherto thought.
Conversely, inactivity markedly decreases collagen turnover in both
tendon and muscle. Chronic loading in the form of
physical training leads both to increased collagen turnover as well
as, dependent on the type of
collagen in question, some degree of net
collagen synthesis. These changes will modify the mechanical
properties and the viscoelastic characteristics of the
tissue, decrease its stress, and likely make it more load resistant.
Cross-linking in connective tissue involves an intimate, enzymatic
interplay between collagen synthesis and ECM proteoglycan components
during growth and maturation and influences the collagen-derived
functional properties of the
tissue. With aging, glycation contributes to additional
cross-linking, which modifies tissue stiffness. Physiological
signaling pathways from mechanical loading to changes in ECM most
likely involve feedback signaling that results in rapid alterations
in the mechanical properties of the
ECM. In developing skeletal muscle, an important interplay
between muscle cells and the ECM is present, and some evidence
from adult human muscle suggests common signaling pathways to
stimulate contractile and ECM components. Unaccustomed overloading
responses suggest an important role
of ECM in the adaptation of
myofibrillar structures in adult muscle.
Development of overuse injury in tendons involves
morphological and biochemical changes including altered collagen
typing and fibril size, hypervascularization zones, accumulation
of nociceptive substances, and impaired
collagen degradation activity. Counteracting these phenomenon
requires adjusted loading rather than absence of
loading in the form of
immobilization. Full understanding of
these physiological processes will provide the physiological basis
for understanding of
tissue overloading and injury seen in both tendons and muscle with
repetitive work and leisure time physical activity.
|
ACKNOWLEDGMENTS |
Peter
Magnusson, Benjamin Miller, and Satu Koskinen are greatly
acknowledged for proofreading.
This work was supported by grants from the Danish Medical Research
Foundation (22–01–0154, 504–14), Ministry of
Culture Foundation for Exercise Research, Copenhagen University
Hospitals Foundation (HS), and NOVO-Nordisk Foundation.
Address for reprint requests and other
correspondence: M. Kjær, Sports Medicine Research Unit, Dept. of
Rheumatology, Copenhagen University Hospital at Bispebjerg, 23 Bispebjerg Bakke,
DK-2400 Copenhagen NV, Denmark (E-mail: m.kjaer{at}mfi.ku.dk
).
|
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2004 by the American Physiological Society.
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