title: Xin-deficient mice display myopathy, impaired contractility, attenuated muscle repair and altered satellite cell functionality.
abstract: OBJECTIVE
  Xin is an F-actin-binding protein expressed during development of cardiac and skeletal muscle. We used Xin-/- mice to determine the impact of Xin deficiency on different aspects of skeletal muscle health, including functionality and regeneration.
  
  
  METHODS
  Xin-/- skeletal muscles and their satellite cell (SC) population were investigated for the presence of myopathic changes by a series of histological and immunofluorescent stains on resting uninjured muscles. To further understand the effect of Xin loss on muscle health and its SCs, we studied SCs responses following cardiotoxin-induced muscle injury. Functional data were determined using in situ muscle stimulation protocol.
  
  
  RESULTS
  Compared to age-matched wild-type (WT), Xin-/- muscles exhibited generalized myopathy and increased fatigability with a significantly decreased force recovery post-fatiguing contractions. Muscle regeneration was attenuated in Xin-/- mice. This impaired regeneration prompted an investigation into SC content and functionality. Although SC content was not different, significantly more activated SCs were present in Xin-/- vs. WT muscles. Primary Xin-/- myoblasts displayed significant reductions (approx. 50%) in proliferative capacity vs. WT; a finding corroborated by significantly decreased MyoD-positive nuclei in 3 days post-injury Xin-/- muscle vs. WT. As more activated SCs did not translate to more proliferating myoblasts, we investigated whether Xin-/- SCs displayed an exaggerated loss by apoptosis. More apoptotic SCs (TUNEL+/Pax7+) were present in Xin-/- muscle vs. WT. Furthermore, more Xin-/- myoblasts were expressing nuclear caspase-3 compared to WT at 3 days post-injury.
  
  
  CONCLUSIONS
  Xin deficiency leads to a myopathic condition characterized by increased muscle fatigability, impaired regeneration and SC dysfunction.
authors.affiliation: Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Al-Sajee
authors.affiliation: Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: A A
authors.initials: AA
authors.lastname: Nissar
authors.affiliation: Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: S K
authors.initials: SK
authors.lastname: Coleman
authors.affiliation: Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: I A
authors.initials: IA
authors.lastname: Rebalka
authors.affiliation: Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Chiang
authors.affiliation: Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Wathra
authors.affiliation: Institute for Cell Biology, University of Bonn, Bonn, Germany.
authors.forename: P F M
authors.initials: PF
authors.lastname: van der Ven
authors.affiliation: Institute for Cell Biology, University of Bonn, Bonn, Germany.
authors.forename: Z
authors.initials: Z
authors.lastname: Orfanos
authors.affiliation: Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: T J
authors.initials: TJ
authors.lastname: Hawke
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000235:genetics*; D018482:Muscle, Skeletal / Q000293:injuries* / Q000502:physiology; D009135:Muscular Diseases / Q000378:metabolism*; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C118478:Xin protein, mouse
keywords: CMYA1; Xirp1; apoptosis; cardiotoxin; cytoskeletal proteins; muscle regeneration