title: Effect of acute and chronic autophagy deficiency on skeletal muscle apoptotic signaling, morphology, and function.
abstract: Autophagy is a catabolic process that targets and degrades cytoplasmic materials. In skeletal muscle, autophagy is required for the control of mass under catabolic conditions, but is also basally active in the maintenance of myofiber homeostasis. In this study, we found that some specific autophagic markers (LC3-I, LC3-II, SQSTM1) were basally lower in glycolytic muscle compared to oxidative muscle of autophagy competent mice. In contrast, basal autophagic flux was higher in glycolytic muscle. In addition, we used several skeletal muscle-specific Atg7 transgenic mouse models to investigate the effect of acute (iAtg7-/-) and chronic (cAtg7-/-) autophagy deficiency on skeletal muscle morphology, contractility, and apoptotic signaling. While acute autophagy ablation (iAtg7-/-) resulted in increased centralized nuclei in glycolytic muscle, it did not alter contractile properties or measures of apoptosis and proteolysis. In contrast, with chronic autophagy deficiency (cAtg7-/-) there was an increased proportion of centralized nuclei, as well as reduced force and altered twitch kinetics in glycolytic muscle. Glycolytic muscle of cAtg7-/-mice also displayed an increased level of the pro-apoptotic protein BAX, as well as calpain and proteasomal enzymatic activity. Collectively, our data demonstrate cumulative damage from chronic skeletal muscle-specific autophagy deficiency with associated apoptotic and proteasomal upregulation. These findings point towards the importance of investigating different muscle/fiber types when studying skeletal muscle autophagy, and the critical role of autophagy in the maintenance of myofiber function, integrity, and cellular health.
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: M F
authors.initials: MF
authors.lastname: Paré
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: B L
authors.initials: BL
authors.lastname: Baechler
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: V A
authors.initials: VA
authors.lastname: Fajardo
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Earl
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Wong
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: T L
authors.initials: TL
authors.lastname: Campbell
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: A R
authors.initials: AR
authors.lastname: Tupling
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada. Electronic address: jquadril@uwaterloo.ca.
authors.forename: J
authors.initials: J
authors.lastname: Quadrilatero
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy / Q000235:genetics*; D000071193:Autophagy-Related Protein 7 / Q000172:deficiency / Q000235:genetics*; D002154:Calpain / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D005786:Gene Expression Regulation; D006019:Glycolysis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D032342:Muscle Cells / Q000378:metabolism* / Q000473:pathology; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D000071456:Sequestosome-1 Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C502661:Atg7 protein, mouse; C494827:Bax protein, mouse; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D051028:bcl-2-Associated X Protein; D002154:Calpain; D046988:Proteasome Endopeptidase Complex; D000071193:Autophagy-Related Protein 7