Structural, biochemical, cellular, and functional changes in skeletal muscle extracellular matrix with aging

Kragstrup, Tue Wenzel; Kjær, Michael; Mackey, Abigail L.

doi:10.1111/j.1600-0838.2011.01377.x

Cited by 182 publications

(159 citation statements)

References 61 publications

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“…Fiber bundle modulus increased from 19.1±5.0 kPa (N=5) in young rats to 39.1±4.2 kPa (N=5) in old rats (Table 1). This increase in longitudinal fiber stiffness is likely to be the result of the increases in endomysium stiffness that occur with age (Kragstrup et al, 2011). There was also a significant effect of age on the transverse stiffness of the aponeuroses (P<0.05).…”

Section: Connective Tissue Propertiesmentioning

confidence: 62%

“…It is thought that the decrease in gear ratio that occurs with increasing force results from muscle transitioning from accommodating shortening by increasing thickness (resisted by the force produced by the fibers), to accommodating shortening by increasing width (resisted by connective tissues). The increases in fiber bundle stiffness, and therefore endomysium stiffness (Kragstrup et al, 2011), and transverse aponeurosis stiffness with age are likely to have increased the resistance of the muscle to bulging and increasing width. This increased resistance may have prevented the normal transition from increasing thickness to increasing width and resulted in gear ratio remaining high in old muscle.…”

Section: Discussionmentioning

confidence: 99%

“…3) decreased with age. Decreases in active muscle stress with age have largely been attributed to an increased contribution of connective tissues (Kjaer, 2004;Gao et al, 2008;Kragstrup et al, 2011) and fat (Kent-Braun et al, 2000) to muscle cross-sectional area. However, the present results suggest that changes in pennation angle during contraction may also contribute to the decrease in stress in old muscles.…”

Section: Discussionmentioning

confidence: 99%

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Stuck in gear: age-related loss of variable gearing in skeletal muscle

Holt

Danos

Roberts

et al. 2016

Journal of Experimental Biology

101

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Skeletal muscles power a broad diversity of animal movements, despite only being able to produce high forces over a limited range of velocities. Pennate muscles use a range of gear ratios, the ratio of muscle shortening velocity to fiber shortening velocity, to partially circumvent these force-velocity constraints. Muscles operate with a high gear ratio at low forces; fibers rotate to greater angles of pennation, enhancing velocity but compromising force. At higher forces, muscles operate with a lower gear ratio; fibers rotate little so limiting muscle shortening velocity, but helping to preserve force. This ability to shift gears is thought to be due to the interplay of contractile force and connective tissue constraints. In order to test this hypothesis, gear ratios were determined in the medial gastrocnemius muscles of both healthy young rats, and old rats where the interaction between contractile and connective tissue properties was assumed to be disrupted. Muscle fiber and aponeurosis stiffness increased with age (P<0.05) from 19.1± 5.0 kPa and 188.5±24.2 MPa, respectively, in young rats to 39.1± 4.2 kPa and 328.0±48.3 MPa in old rats, indicating a mechanical change in the interaction between contractile and connective tissues. Gear ratio decreased with increasing force in young (P<0.001) but not old (P=0.72) muscles, indicating that variable gearing is lost in old muscle. These findings support the hypothesis that variable gearing results from the interaction between contractile and connective tissues and suggest novel explanations for the decline in muscle performance with age.

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Section: Connective Tissue Propertiesmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Stuck in gear: age-related loss of variable gearing in skeletal muscle

Holt

Danos

Roberts

et al. 2016

Journal of Experimental Biology

101

View full text Add to dashboard Cite

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“…In addition, such testing allows for calculation of the anisotropy ratio, which provides a standard metric for macroscopic tissue deformation (Courtney et al ., 2006). Finally, the biaxial testing and sample preparation protocol eliminates the mechanical contribution of the tendon, which may confound results (Kragstrup et al ., 2011). Calculation of the anisotrophy ratio following biaxial testing revealed a decreased degree of anisotropy in aged skeletal muscle.…”

Section: Resultsmentioning

confidence: 99%

Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion

et al. 2017

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SummaryAge‐related declines in skeletal muscle regeneration have been attributed to muscle stem cell (MuSC) dysfunction. Aged MuSCs display a fibrogenic conversion, leading to fibrosis and impaired recovery after injury. Although studies have demonstrated the influence of in vitro substrate characteristics on stem cell fate, whether and how aging of the extracellular matrix (ECM) affects stem cell behavior has not been investigated. Here, we investigated the direct effect of the aged muscle ECM on MuSC lineage specification. Quantification of ECM topology and muscle mechanical properties reveals decreased collagen tortuosity and muscle stiffening with increasing age. Age‐related ECM alterations directly disrupt MuSC responses, and MuSCs seeded ex vivo onto decellularized ECM constructs derived from aged muscle display increased expression of fibrogenic markers and decreased myogenicity, compared to MuSCs seeded onto young ECM. This fibrogenic conversion is recapitulated in vitro when MuSCs are seeded directly onto matrices elaborated by aged fibroblasts. When compared to young fibroblasts, fibroblasts isolated from aged muscle display increased nuclear levels of the mechanosensors, Yes‐associated protein (YAP)/transcriptional coactivator with PDZ‐binding motif (TAZ), consistent with exposure to a stiff microenvironment in vivo. Accordingly, preconditioning of young fibroblasts by seeding them onto a substrate engineered to mimic the stiffness of aged muscle increases YAP/TAZ nuclear translocation and promotes secretion of a matrix that favors MuSC fibrogenesis. The findings here suggest that an age‐related increase in muscle stiffness drives YAP/TAZ‐mediated pathogenic expression of matricellular proteins by fibroblasts, ultimately disrupting MuSC fate.

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“…The importance of the interaction between contractile muscle cells and the extracellular matrix (ECM) has received significant attention over the past two decades [1][2][3][4][5]. In particular, the ECM is thought to play a critical role in enabling force transmission from fibres to tendons and in the protection of muscle cells from excessive damage during muscle contractions.…”

Section: Introductionmentioning

confidence: 99%

Multiscale models of skeletal muscle reveal the complex effects of muscular dystrophy on tissue mechanics and damage susceptibility

et al. 2015

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Computational models have been increasingly used to study the tissue-level constitutive properties of muscle microstructure; however, these models were not created to study or incorporate the influence of disease-associated modifications in muscle. The purpose of this paper was to develop a novel multiscale muscle modelling framework to elucidate the relationship between microstructural disease adaptations and modifications in both mechanical properties of muscle and strain in the cell membrane. We used an agent-based model to randomly generate new muscle fibre geometries and mapped them into a finite-element model representing a cross section of a muscle fascicle. The framework enabled us to explore variability in the shape and arrangement of fibres, as well as to incorporate disease-related changes. We applied this method to reveal the trade-offs between mechanical properties and damage susceptibility in Duchenne muscular dystrophy (DMD). DMD is a fatal genetic disease caused by a lack of the transmembrane protein dystrophin, leading to muscle wasting and death due to cardiac or pulmonary complications. The most prevalent microstructural variations in DMD include: lack of transmembrane proteins, fibrosis, fatty infiltration and variation in fibre cross-sectional area. A parameter analysis of these variations and case study of DMD revealed that the nature of fibrosis and density of transmembrane proteins strongly affected the stiffness of the muscle and susceptibility to membrane damage.

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Structural, biochemical, cellular, and functional changes in skeletal muscle extracellular matrix with aging

Cited by 182 publications

References 61 publications

Stuck in gear: age-related loss of variable gearing in skeletal muscle

Stuck in gear: age-related loss of variable gearing in skeletal muscle

Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion

Multiscale models of skeletal muscle reveal the complex effects of muscular dystrophy on tissue mechanics and damage susceptibility

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