Sports Medicine Research Unit, Department of Rheumatology, Copenhagen University Hospital at Bispebjerg, Copenhagen, Denmark
Kjær, Michael. Role of Extracellular Matrix in Adaptation of Tendon and ...Skeletal Muscle to Mechanical Loading. Physiol Rev 84: 649698, 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.
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 ).
Collagens are the most abundant components of the extracellular matrix and many types of soft tissues. Elastin is another major component of certain soft tissues, such as arterial walls and ...ligaments. Many other molecules, though lower in quantity, function as essential components of the extracellular matrix in soft tissues. Some of these are reviewed in this chapter. Besides their basic structure, biochemistry and physiology, their roles in disorders of soft tissues are discussed only briefly as most chapters in this volume deal with relevant individual compounds. Fibronectin with its muldomain structure plays a role of "master organizer" in matrix assembly as it forms a bridge between cell surface receptors, e.g., integrins, and compounds such collagen, proteoglycans and other focal adhesion molecules. It also plays an essential role in the assembly of fibrillin-1 into a structured network. Laminins contribute to the structure of the extracellular matrix (ECM) and modulate cellular functions such as adhesion, differentiation, migration, stability of phenotype, and resistance towards apoptosis. Though the primary role of fibrinogen is in clot formation, after conversion to fibrin by thrombin, it also binds to a variety of compounds, particularly to various growth factors, and as such fibrinogen is a player in cardiovascular and extracellular matrix physiology. Elastin, an insoluble polymer of the monomeric soluble precursor tropoelastin, is the main component of elastic fibers in matrix tissue where it provides elastic recoil and resilience to a variety of connective tissues, e.g., aorta and ligaments. Elastic fibers regulate activity of TGFβs through their association with fibrillin microfibrils. Elastin also plays a role in cell adhesion, cell migration, and has the ability to participate in cell signaling. Mutations in the elastin gene lead to cutis laxa. Fibrillins represent the predominant core of the microfibrils in elastic as well as non-elastic extracellular matrixes, and interact closely with tropoelastin and integrins. Not only do microfibrils provide structural integrity of specific organ systems, but they also provide a scaffold for elastogenesis in elastic tissues. Fibrillin is important for the assembly of elastin into elastic fibers. Mutations in the fibrillin-1 gene are closely associated with Marfan syndrome. Fibulins are tightly connected with basement membranes, elastic fibers and other components of extracellular matrix and participate in formation of elastic fibers. Tenascins are ECM polymorphic glycoproteins found in many connective tissues in the body. Their expression is regulated by mechanical stress both during development and in adulthood. Tenascins mediate both inflammatory and fibrotic processes to enable effective tissue repair and play roles in pathogenesis of Ehlers-Danlos, heart disease, and regeneration and recovery of musculo-tendinous tissue. One of the roles of thrombospondin 1 is activation of TGFβ. Increased expression of thrombospondin and TGFβ activity was observed in fibrotic skin disorders such as keloids and scleroderma. Cartilage oligomeric matrix protein (COMP) or thrombospondin-5 is primarily present in the cartilage. High levels of COMP are present in fibrotic scars and systemic sclerosis of the skin, and in tendon, especially with physical activity, loading and post-injury. It plays a role in vascular wall remodeling and has been found in atherosclerotic plaques as well.
Background:
Previous studies have shown that eccentric training has a positive effect on Achilles tendinopathy, but few randomized controlled trials have compared it with other loading-based ...treatment regimens.
Purpose:
To evaluate the effectiveness of eccentric training (ECC) and heavy slow resistance training (HSR) among patients with midportion Achilles tendinopathy.
Study Design:
Randomized controlled trial; Level of evidence, 1.
Methods:
A total of 58 patients with chronic (>3 months) midportion Achilles tendinopathy were randomized to ECC or HSR for 12 weeks. Function and symptoms (Victorian Institute of Sports Assessment–Achilles), tendon pain during activity (visual analog scale), tendon swelling, tendon neovascularization, and treatment satisfaction were assessed at 0 and 12 weeks and at the 52-week follow-up. Analyses were performed on an intention-to-treat basis.
Results:
Both groups showed significant (P < .0001) improvements in Victorian Institute of Sports Assessment–Achilles and visual analog scale from 0 to 12 weeks, and these improvements were maintained at the 52-week follow-up. Concomitant with the clinical improvement, there was a significant reduction in tendon thickness and neovascularization. None of these robust clinical and structural improvements differed between the ECC and HSR groups. However, patient satisfaction tended to be greater after 12 weeks with HSR (100%) than with ECC (80%; P = .052) but not after 52 weeks (HSR, 96%; ECC, 76%; P = .10), and the mean training session compliance rate was 78% in the ECC group and 92% in the HSR group, with a significant difference between groups (P < .005).
Conclusion:
The results of this study show that both traditional ECC and HSR yield positive, equally good, lasting clinical results in patients with Achilles tendinopathy and that the latter tends to be associated with greater patient satisfaction after 12 weeks but not after 52 weeks.
The morphology of articular cartilage (AC) enables painless movement. Aging and mechanical loading are believed to influence development of osteoarthritis (OA), yet the connection remains unclear.
...This narrative review describes the current knowledge regarding this area, with the literature search made on PubMed using appropriate keywords regarding AC, age, and mechanical loading.
Following skeletal maturation, chondrocyte numbers decline while increasing senescence occurs. Lower cartilage turnover causes diminished maintenance capacity, which produces accumulation of fibrillar crosslinks by advanced glycation end products, resulting in increased stiffness and thereby destruction susceptibility.
Mechanical loading changes proteoglycan content. Moderate mechanical loading causes hypertrophy and reduced mechanical loading causes atrophy. Overloading produces collagen network damage and proteoglycan loss, leading to irreversible cartilage destruction because of lack of regenerative capacity. Catabolic pathways involve inflammation and the transcription factor nuclear factor-κB. Thus, age seems to be a predisposing factor for OA, with mechanical overload being the likely triggering cause.
Women differ from men with regard to muscle and tendon, most likely because of sex differences in estrogen. The present experimental findings suggest the hypothesis that estrogen has an anabolic ...effect on muscle primarily by lowering the protein turnover and enhancing sensitivity to resistance training. Furthermore, estrogen may reduce the stiffness of tendons, an effect that may be modified by physical training.
Effect of aging and exercise on the tendon Svensson, Rene B; Heinemeier, Katja Maria; Couppé, Christian ...
Journal of applied physiology (1985),
2016-Dec-01, 2016-12-01, 20161201, Letnik:
121, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Here, we review the literature on how tendons respond and adapt to ageing and exercise. With respect to aging, there are considerable changes early in life, but this seems to be maturation rather ...than aging per se. In vitro data indicate that aging is associated with a decreased potential for cell proliferation and a reduction in the number of stem/progenitor-like cells. Further, there is persuasive evidence that turnover in the core of the tendon after maturity is very slow or absent. Tendon fibril diameter, collagen content, and whole tendon size appear to be largely unchanged with aging, while glycation-derived cross-links increase substantially. Mechanically, aging appears to be associated with a reduction in modulus and strength. With respect to exercise, tendon cells respond by producing growth factors, and there is some support for a loading-induced increase in tendon collagen synthesis in humans, which likely reflects synthesis at the very periphery of the tendon rather than the core. Average collagen fibril diameter is largely unaffected by exercise, while there can be some hypertrophy of the whole tendon. In addition, it seems that resistance training can yield increased stiffness and modulus of the tendon and may reduce the amount of glycation. Exercise thereby tends to counteract the effects of aging.
Key points
Accumulation of skeletal muscle extracellular matrix is an unfavourable characteristic of many muscle diseases, muscle injury and sarcopenia.
The extent of cross‐talk between fibroblasts, ...as the source of matrix protein, and satellite cells in humans is unknown. We studied this in human muscle biopsies and cell‐culture studies.
We observed a strong stimulation of myogenesis by human fibroblasts in cell culture.
In biopsies collected 30 days after a muscle injury protocol, fibroblast number increased to four times control levels, where fibroblasts were found to be preferentially located immediately surrounding regenerating muscle fibres.
These novel findings indicate an important role for fibroblasts in supporting the regeneration of muscle fibres, potentially through direct stimulation of satellite cell differentiation and fusion, and contribute to understanding of cell–cell cross‐talk during physiological and pathological muscle remodelling.
Accumulation of skeletal muscle extracellular matrix is an unfavourable characteristic of many muscle diseases, muscle injury and sarcopenia. In addition to the indispensable role satellite cells play in muscle regeneration, there is emerging evidence in rodents for a regulatory influence on fibroblast activity. However, the influence of fibroblasts on satellite cells and muscle regeneration in humans is unknown. The purpose of this study was to investigate this in vitro and during in vivo regeneration in humans. Following a muscle injury protocol in young healthy men (n = 7), the number of fibroblasts (TCF7L2+), satellite cells (Pax7+), differentiating myogenic cells (myogenin+) and regenerating fibres (neonatal/embryonic myosin+) was determined from biopsy cross‐sections. Fibroblasts and myogenic precursor cells (MPCs) were also isolated from human skeletal muscle (n = 4) and co‐cultured using different cell ratios, with the two cell populations either in direct contact with each other or separated by a permeable membrane. MPC proliferation, differentiation and fusion were assessed from cells stained for BrdU, desmin and myogenin. On biopsy cross‐sections, fibroblast number was seen to increase, along with myogenic cell number, by d7 and increase further by d30, where fibroblasts were observed to be preferentially located immediately surrounding regenerating muscle fibres. In vitro, the presence of fibroblasts in direct contact with MPCs was found to moderately stimulate MPC proliferation and strongly stimulate both MPC differentiation and MPC fusion. It thus appears, in humans, that fibroblasts exert a strong positive regulatory influence on MPC activity, in line with observations during in vivo skeletal muscle regeneration.
Key points
Accumulation of skeletal muscle extracellular matrix is an unfavourable characteristic of many muscle diseases, muscle injury and sarcopenia.
The extent of cross‐talk between fibroblasts, as the source of matrix protein, and satellite cells in humans is unknown. We studied this in human muscle biopsies and cell‐culture studies.
We observed a strong stimulation of myogenesis by human fibroblasts in cell culture.
In biopsies collected 30 days after a muscle injury protocol, fibroblast number increased to four times control levels, where fibroblasts were found to be preferentially located immediately surrounding regenerating muscle fibres.
These novel findings indicate an important role for fibroblasts in supporting the regeneration of muscle fibres, potentially through direct stimulation of satellite cell differentiation and fusion, and contribute to understanding of cell–cell cross‐talk during physiological and pathological muscle remodelling.
Macrophages (MPs) exert either beneficial or deleterious effects on tissue repair, depending on their activation/polarization state. They are crucial for adult skeletal muscle repair, notably by ...acting on myogenic precursor cells. However, these interactions have not been fully characterized. Here, we explored both in vitro and in vivo, in human, the interactions of differentially activated MPs with myogenic precursor cells (MPCs) during adult myogenesis and skeletal muscle regeneration. We showed in vitro that through the differential secretion of cytokines and growth factors, proinflammatory MPs inhibited MPC fusion while anti‐inflammatory MPs strongly promoted MPC differentiation by increasing their commitment into differentiated myocytes and the formation of mature myotubes. Furthermore, the in vivo time course of expression of myogenic and MP markers was studied in regenerating human healthy muscle after damage. We observed that regenerating areas containing proliferating MPCs were preferentially associated with MPs expressing proinflammatory markers. In the same muscle, regenerating areas containing differentiating myogenin‐positive MPCs were preferentially coupled to MPs harboring anti‐inflammatory markers. These data demonstrate for the first time in human that MPs sequentially orchestrate adult myogenesis during regeneration of damaged skeletal muscle. These results support the emerging concept that inflammation, through MP activation, controls stem cell fate and coordinates tissue repair. STEM CELLS2013;31:384–396
The poor regenerative capacity of articular cartilage presents a major clinical challenge and may relate to a limited turnover of the cartilage collagen matrix. However, the collagen turnover rate ...during life is not clear, and it is debated whether osteoarthritis (OA) can influence it. Using the carbon-14 ((14)C) bomb-pulse method, life-long replacement rates of collagen were measured in tibial plateau cartilage from 23 persons born between 1935 and1997 (15 and 8 persons with OA and healthy cartilage, respectively). The (14)C levels observed in cartilage collagen showed that, virtually, no replacement of the collagen matrix happened after skeletal maturity and that neither OA nor tissue damage, per se, influenced collagen turnover. Regional differences in (14)C content across the joint surface showed that cartilage collagen located centrally on the joint surface is formed several years earlier than collagen located peripherally. The collagen matrix of human articular cartilage is an essentially permanent structure that has no significant turnover in adults, even with the occurrence of disease.
AIMThis study aimed to examine changes in lean mass during hospitalization in geriatric patients and the effect of muscle activation by neuromuscular electrical stimulation.
METHODSThirteen patients ...(69–94 yr) at a geriatric ward completed tests at hospital admission (days 2–3) and discharge (days 8–10). One leg received daily stimulation of the knee extensors, whereas the other leg served as a control leg. Lean mass was evaluated by dual-energy x-ray absorptiometry scans and muscle thickness by ultrasound scans. Muscle biopsies were collected from both legs at admission and discharge in nine patients and analyzed for fiber size, satellite cell number, and activation and expression of genes associated with muscle protein synthesis and breakdown, connective tissue, and cellular stress.
RESULTSThe relative decline in leg lean mass and midthigh region lean mass was larger in the control (−2.8% ± 1.5%) versus the stimulated leg (−0.5% ± 1.4%, P < 0.05). Although there were no changes in fiber size or satellite cell number, the mRNA data revealed that, compared with control, the stimulation resulted in a downregulation of myostatin (P < 0.05) and a similar trend for MAFbx (P = 0.099), together with an upregulation of Collagen I (P < 0.001), TenascinC (P < 0.001), CD68 (P < 0.01), and Ki67 (P < 0.05) mRNA.
CONCLUSIONThese findings demonstrate a moderate decline in leg lean mass during a hospital stay in geriatric patients, whereas leg lean mass was preserved with daily neuromuscular electrical muscle activation. At the cellular level, the stimulation had a clear influence on suppression of atrophy signaling pathways in parallel with a stimulation of connective tissue and cellular remodeling processes.
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