title: Increased Stiffness in Aged Skeletal Muscle Impairs Muscle Progenitor Cell Proliferative Activity.
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.
authors: Centre Hospitalier de l'Université de Sherbrooke Research Center (CRCHUS), Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors: Grégory
authors: G
authors: Lacraz
authors: Centre Hospitalier de l'Université de Sherbrooke Research Center (CRCHUS), Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors: André-Jean
authors: AJ
authors: Rouleau
authors: Centre Hospitalier de l'Université de Sherbrooke Research Center (CRCHUS), Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors: Vanessa
authors: V
authors: Couture
authors: Department of Electrical and Computer Engineering, Faculty of Engineering, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors: Thomas
authors: T
authors: Söllrald
authors: Centre Hospitalier de l'Université de Sherbrooke Research Center (CRCHUS), Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors: Geneviève
authors: G
authors: Drouin
authors: Centre Hospitalier de l'Université de Sherbrooke Research Center (CRCHUS), Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors: Noémie
authors: N
authors: Veillette
authors: Centre Hospitalier de l'Université de Sherbrooke Research Center (CRCHUS), Université de Sherbrooke, Sherbrooke, Quebec, Canada; Department of Pharmacology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors: Michel
authors: M
authors: Grandbois
authors: Centre Hospitalier de l'Université de Sherbrooke Research Center (CRCHUS), Université de Sherbrooke, Sherbrooke, Quebec, Canada; Department of Orthopedic Surgery, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors: Guillaume
authors: G
authors: Grenier
mesh_terms: D000375:Aging; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D024510:Muscle Development; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000502:physiology; D018482:Muscle, Skeletal / Q000166:cytology* / Q000502:physiology*; D032446:Myoblasts / Q000166:cytology* / Q000502:physiology; D012038:Regeneration