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Journal ArticleDOI

Elucidation of extracellular matrix mechanics from muscle fibers and fiber bundles.

24 Feb 2011-Journal of Biomechanics (Elsevier)-Vol. 44, Iss: 4, pp 771-773

TL;DR: A new method to quantify viscoelastic ECM modulus is presented by combining tests of single muscle fibers and fiber bundles, which demonstrate that ECM is a highly nonlinearly elastic material, while muscle fibers are linearly elastic.

AbstractThe importance of the extracellular matrix (ECM) in muscle is widely recognized, since ECM plays a central role in proper muscle development (Buck and Horwitz, 1987), tissue structural support (Purslow, 2002), and transmission of mechanical signals between fibers and tendon (Huijing, 1999). Since substrate biomechanical properties have been shown to be critical in the biology of tissue development and remodeling (Engler et al., 2006; Gilbert et al., 2010), it is likely that mechanics are critical for ECM to perform its function. Unfortunately, there are almost no data available regarding skeletal muscle ECM viscoelastic properties. This is primarily due to the impossibility of isolating and testing muscle ECM. Therefore, this note presents a new method to quantify viscoelastic ECM modulus by combining tests of single muscle fibers and fiber bundles. Our results demonstrate that ECM is a highly nonlinearly elastic material, while muscle fibers are linearly elastic.

Topics: Skeletal muscle (53%)

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Citations
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Journal ArticleDOI
TL;DR: The structure, composition, and mechanical properties of skeletal muscle ECM are reviewed; the cells that contribute to the maintenance of the ECMAreas for future study are proposed; and overview changes that occur with pathology are described.
Abstract: The skeletal muscle extracellular matrix (ECM) plays an important role in muscle fiber force transmission, maintenance, and repair. In both injured and diseased states, ECM adapts dramatically, a property thathas clinical manifestations and alters muscle function. Here, we review the structure, composition, and mechanical properties of skeletal muscle ECM, describe the cells that contribute to the maintenance of the ECM and, finally, overview changes that occur with pathology. New scanning electron micrographs of ECM structure are also presented with hypotheses about ECM structure-function relationships. Detailed structure-function relationships of the ECM have yet to be defined and, as a result, we propose areas for future studies.

593 citations


Cites methods from "Elucidation of extracellular matrix..."

  • ...The ECM modulus can then be calculated using the rule of mixtures for composites after the load-bearing area of fiber and ECM are first defined.(79) Using this approach, isolated muscle fiber stress–strain behavior was shown to be linear, and muscle bundle stress–strain behavior...

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Journal ArticleDOI
TL;DR: approaches used to study fibrosis in tissues, such as lung, kidney, and liver, need to be applied to studies of skeletal muscle to identify ways to prevent or even cure the devastating maladies of skeletal Muscle Fibrosis.
Abstract: Skeletal muscle fibrosis can be a devastating clinical problem that arises from many causes, including primary skeletal muscle tissue diseases, as seen in the muscular dystrophies, or it can be secondary to events that include trauma to muscle or brain injury The cellular source of activated fibroblasts (myofibroblasts) may include resident fibroblasts, adult muscle stem cells, or inflammatory or perivascular cells, depending on the model studied Even though it is likely that there is no single source for all myofibroblasts, a common mechanism for the production of fibrosis is via the transforming growth factor-β/phosphorylated Smad3 pathway This pathway and its downstream targets thus provide loci for antifibrotic therapies, as do methods for blocking the transdifferentiation of progenitors into activated fibroblasts A structural model for the extracellular collagen network of skeletal muscle is needed so that measurements of collagen content, morphology, and gene expression can be related to mechanical properties Approaches used to study fibrosis in tissues, such as lung, kidney, and liver, need to be applied to studies of skeletal muscle to identify ways to prevent or even cure the devastating maladies of skeletal muscle

195 citations


Cites background from "Elucidation of extracellular matrix..."

  • ...Furthermore, the fiber groups bore the same stress (force/area), even though they were 10–20 times larger than the single fibers (86)....

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Journal ArticleDOI
TL;DR: Findings indicate that theECM of tibialis anterior muscles from old mice has a higher modulus than the ECM of adult muscles, likely driven by an accumulation of densely packed extensively crosslinked collagen.
Abstract: Advanced age is associated with increases in muscle passive stiffness, but the contributors to the changes remain unclear. Our purpose was to determine the relative contributions of muscle fibers and extracellular matrix (ECM) to muscle passive stiffness in both adult and old animals. Passive mechanical properties were determined for isolated individual muscle fibers and bundles of muscle fibers that included their associated ECM, obtained from tibialis anterior muscles of adult (8–12 mo old) and old (28–30 mo old) mice. Maximum tangent moduli of individual muscle fibers from adult and old muscles were not different at any sarcomere length tested. In contrast, the moduli of bundles of fibers from old mice was more than twofold greater than that of fiber bundles from adult muscles at sarcomere lengths >2.5 μm. Because ECM mechanical behavior is determined by the composition and arrangement of its molecular constituents, we also examined the effect of aging on ECM collagen characteristics. With aging, muscle ECM hydroxyproline content increased twofold and advanced glycation end-product protein adducts increased threefold, whereas collagen fibril orientation and total ECM area were not different between muscles from adult and old mice. Taken together, these findings indicate that the ECM of tibialis anterior muscles from old mice has a higher modulus than the ECM of adult muscles, likely driven by an accumulation of densely packed extensively crosslinked collagen.

122 citations


Cites background or methods or result from "Elucidation of extracellular matrix..."

  • ...Using the rule of mixtures (22), the corresponding contributions of ECM and muscle fibers to the passive stiffness of muscles of old mice is 73% ECM and 27% fibers....

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  • ...Previous estimates of ECM stiffness for muscles of young adult mice have compared mechanical properties of single muscle fibers with those of muscle fiber bundles that include fibers and their surrounding ECM (22)....

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  • ...Our data are in contrast to previous reports of a sixfold greater modulus of muscle fiber bundles compared with single fibers from adult mice as well as a linear stress-strain response of single fibers (22)....

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  • ...In the present study, we report the tangent modulus at four different strains, with a maximum strain of 24%, whereas the previous study (22) reports quadratic modulus with maximum strains of 100%....

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  • ...Given that the modulus of groups of fibers with their associated ECM removed is similar to that of single fibers (22), we are confident that this approach to determining the material properties of ECM is valid....

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Journal ArticleDOI
TL;DR: It is concluded that muscle fibrosis does not lead to increased passive stiffness and that collagen content is not predictive of muscle stiffness.
Abstract: Many skeletal muscle diseases are associated with progressive fibrosis leading to impaired muscle function. Collagen within the extracellular matrix is the primary structural protein providing a me...

86 citations


Cites background from "Elucidation of extracellular matrix..."

  • ...Passive stiffness in mammalian skeletal muscle is thought to be determined largely by ECM collagen, although intracellular elements are also known to contribute (13, 14, 30)....

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  • ...Recent studies have suggested that the ECM is primarily responsible for passive stiffness in mammalian skeletal muscle (13, 14, 30); however, intracellular components may also contribute (37)....

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Journal ArticleDOI
21 Aug 2015-PLOS ONE
TL;DR: Findings provide novel evidence that the low regenerative potential of aged skeletal muscle is independent of intrinsic MPC properties but is related to the increase in the stiffness of the MPC microenvironment.
Abstract: Background Skeletal muscle aging is associated with a decreased regenerative potential due to the loss of function of endogenous stem cells or myogenic progenitor cells (MPCs). Aged skeletal muscle is characterized by the deposition of extracellular matrix (ECM), which in turn influences the biomechanical properties of myofibers by increasing their stiffness. Since the stiffness of the MPC microenvironment directly impacts MPC function, we hypothesized that the increase in muscle stiffness that occurs with aging impairs the behavior of MPCs, ultimately leading to a decrease in regenerative potential. Results We showed that freshly isolated individual myofibers from aged mouse muscles contain fewer MPCs overall than myofibers from adult muscles, with fewer quiescent MPCs and more proliferative and differentiating MPCs. We observed alterations in cultured MPC behavior in aged animals, where the proliferation and differentiation of MPCs were lower and higher, respectively. These alterations were not linked to the intrinsic properties of aged myofibers, as shown by the similar values for the cumulative population-doubling values and fusion indexes. However, atomic force microscopy (AFM) indentation experiments revealed a nearly 4-fold increase in the stiffness of the MPC microenvironment. We further showed that the increase in stiffness is associated with alterations to muscle ECM, including the accumulation of collagen, which was correlated with higher hydroxyproline and advanced glycation end-product content. Lastly, we recapitulated the impaired MPC behavior observed in aging using a hydrogel substrate that mimics the stiffness of myofibers. Conclusions These findings provide novel evidence that the low regenerative potential of aged skeletal muscle is independent of intrinsic MPC properties but is related to the increase in the stiffness of the MPC microenvironment.

68 citations


References
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Journal ArticleDOI
25 Aug 2006-Cell
TL;DR: Naive mesenchymal stem cells are shown here to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity, consistent with the elasticity-insensitive commitment of differentiated cell types.
Abstract: Microenvironments appear important in stem cell lineage specification but can be difficult to adequately characterize or control with soft tissues. Naive mesenchymal stem cells (MSCs) are shown here to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity. Soft matrices that mimic brain are neurogenic, stiffer matrices that mimic muscle are myogenic, and comparatively rigid matrices that mimic collagenous bone prove osteogenic. During the initial week in culture, reprogramming of these lineages is possible with addition of soluble induction factors, but after several weeks in culture, the cells commit to the lineage specified by matrix elasticity, consistent with the elasticity-insensitive commitment of differentiated cell types. Inhibition of nonmuscle myosin II blocks all elasticity-directed lineage specification-without strongly perturbing many other aspects of cell function and shape. The results have significant implications for understanding physical effects of the in vivo microenvironment and also for therapeutic uses of stem cells.

11,028 citations


"Elucidation of extracellular matrix..." refers background in this paper

  • ...Since substrate biomechanical properties have been shown to be critical in the biology of tissue development and remodeling (Engler et al., 2006; Gilbert et al., 2010), it is likely that mechanics are critical for ECM to perform its function....

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Journal ArticleDOI
27 Aug 2010-Science
TL;DR: Using a bioengineered substrate to recapitulate key biophysical and biochemical niche features in conjunction with a highly automated single-cell tracking algorithm, it is shown that substrate elasticity is a potent regulator of MuSC fate in culture.
Abstract: Stem cells that naturally reside in adult tissues, such as muscle stem cells (MuSCs), exhibit robust regenerative capacity in vivo that is rapidly lost in culture. Using a bioengineered substrate to recapitulate key biophysical and biochemical niche features in conjunction with a highly automated single-cell tracking algorithm, we show that substrate elasticity is a potent regulator of MuSC fate in culture. Unlike MuSCs on rigid plastic dishes (approximately 10(6) kilopascals), MuSCs cultured on soft hydrogel substrates that mimic the elasticity of muscle (12 kilopascals) self-renew in vitro and contribute extensively to muscle regeneration when subsequently transplanted into mice and assayed histologically and quantitatively by noninvasive bioluminescence imaging. Our studies provide novel evidence that by recapitulating physiological tissue rigidity, propagation of adult muscle stem cells is possible, enabling future cell-based therapies for muscle-wasting diseases.

1,282 citations


"Elucidation of extracellular matrix..." refers background in this paper

  • ...Since substrate biomechanical properties have been shown to be critical in the biology of tissue development and remodeling (Engler et al., 2006; Gilbert et al., 2010), it is likely that mechanics are critical for ECM to perform its function....

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Journal ArticleDOI
01 Jun 2009-Bone

1,128 citations


"Elucidation of extracellular matrix..." refers background in this paper

  • ...Since substrate biomechanical properties have been shown to be critical in the biology of tissue development and remodeling (Engler et al., 2006; Gilbert et al., 2010), it is likely that mechanics are critical for ECM to perform its function....

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Journal ArticleDOI
TL;DR: Avian integrin shows little specificity and appears to behave as a multifunctional, promiscuous receptor for extracellular matrix molecules, and post-translational modifications provide yet another mechanism for regulating integrin-ligand binding.
Abstract: Table 2 lists most of the extracellular matrix and related receptors identified to date. The wide range of binding affinities of these receptors for their ligands may be important to their function. The affinity of integrins for fibronectin is moderate, with a dissociation constant in the micromolar range. This affinity level leads to relatively rapid dissociation and reformation of receptor-ligand complexes. Thus changes in component concentration can shift binding equilibria within minutes (the time scale of many biologic phenomena) and change the number or organization of adhesive complexes. This type of interaction would be useful in motile cells, in which adhesions must form and dissociate rapidly. In contrast, the affinity of the 68-kDa laminin receptor for its ligand is three orders of magnitude higher. Such levels of affinity would be useful in stabilizing tissue. Members of the integrin family appear to recognize an RGD sequence on the ligands to which they bind. Since there are many ligands containing the RGD sequence, the question of specificity arises. Avian integrin shows little specificity and appears to behave as a multifunctional, promiscuous receptor for extracellular matrix molecules. Figure 1 summarizes our current view of the structural and functional features of avian integrin. In contrast, the mammalian receptors for vitronectin and fibronectin are specific for their respective ligands. More than one of these receptors may be present simultaneously on a cell surface, e.g. fibroblasts express receptors for fibronectin, laminin, and vitronectin at the same time. This multiplicity of receptors provides potential mechanisms for generating the adhesive differences among cells believed to play a prominent role in morphogenesis. Further adhesive differences may stem from the formation of different combinations of various alpha- and beta-subunits expressed in the cell. The mechanism of regulation of adhesive interactions with the extracellular matrix is only beginning to be explored. There are several levels at which this regulation might occur. Integrin appears to be more regionalized in more developed cells that are integral parts of tissue structures. Changes in receptor distribution could alter the relative strength of adhesive interactions. In certain instances, avian integrin disappears, or its concentration is reduced, e.g. during the development of embryonic lung (Chen et al 1986) and erythroid cells (Patel & Lodish 1985). Post-translational modifications provide yet another mechanism for regulating integrin-ligand binding.(ABSTRACT TRUNCATED AT 400 WORDS)

781 citations


"Elucidation of extracellular matrix..." refers background in this paper

  • ...Extracellular matrix (ECM) is essential for the development, maintenance and regeneration of skeletal muscle (Buck and Horwitz, 1987; Purslow, 2002)....

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  • ...The importance of the extracellular matrix (ECM) in muscle is widely recognized, since ECM plays a central role in proper muscle development (Buck and Horwitz, 1987), tissue structural support (Purslow, 2002), and transmission ofmechanical signals between fibers and tendon (Huijing, 1999)....

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  • ...…r a c t The importance of the extracellular matrix (ECM) in muscle is widely recognized, since ECM plays a central role in proper muscle development (Buck and Horwitz, 1987), tissue structural support (Purslow, 2002), and transmission ofmechanical signals between fibers and tendon (Huijing, 1999)....

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Journal ArticleDOI
TL;DR: The passive tension-sarcomere length relation of rat cardiac muscle was investigated by studying passive (or not activated) single myocytes and trabeculae and the contribution of collagen, titin, microtubules, and intermediate filaments to tension and stiffness was investigated.
Abstract: The passive tension-sarcomere length relation of rat cardiac muscle was investigated by studying passive (or not activated) single myocytes and trabeculae. The contribution of collagen, titin, microtubules, and intermediate filaments to tension and stiffness was investigated by measuring (1) the effects of KCl/KI extraction on both trabeculae and single myocytes, (2) the effect of trypsin digestion on single myocytes, and (3) the effect of colchicine on single myocytes. It was found that over the working range of sarcomeres in the heart (lengths approximately 1.9–2.2 microns), collagen and titin are the most important contributors to passive tension with titin dominating at the shorter end of the working range and collagen at longer lengths. Microtubules made a modest contribution to passive tension in some cells, but on average their contribution was not significant. Finally, intermediate filaments contributed about 10% to passive tension of trabeculae at sarcomere lengths from approximately 1.9 to 2.1 microns, and their contribution dropped to only a few percent at longer lengths. At physiological sarcomere lengths of the heart, cardiac titin developed much higher tensions (> 20-fold) than did skeletal muscle titin at comparable lengths. This might be related to the finding that cardiac titin has a molecular mass of 2.5 MDa, 0.3–0.5 MDa smaller than titin of mammalian skeletal muscle, which is predicted to result in a much shorter extensible titin segment in the I-band of cardiac muscle. Passive stress plotted versus the strain of the extensible titin segment showed that the stress-strain relationships are similar in cardiac and skeletal muscle. The difference in passive stress between cardiac and skeletal muscle at the sarcomere level predominantly resulted from much higher strains of the I-segment of cardiac titin at a given sarcomere length. By expressing a smaller titin isoform, without changing the properties of the molecule itself, cardiac muscle is able to develop significant levels of passive tension at physiological sarcomere lengths.

554 citations


"Elucidation of extracellular matrix..." refers methods in this paper

  • ...Previous studies used methods of subtraction, where the ECM was ‘‘preferentially’’ digested from muscle and its properties inferred from subtracting the digested state from the undigested state (see review by Fomovsky et al., 2010; Granzier and Irving, 1995)....

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