title: Apoptosis and necrosis mediate skeletal muscle fiber loss in age-induced mitochondrial enzymatic abnormalities.
abstract: Sarcopenia, the age-induced loss of skeletal muscle mass and function, results from the contributions of both fiber atrophy and loss of myofibers. We have previously characterized sarcopenia in FBN rats, documenting age-dependent declines in muscle mass and fiber number along with increased fiber atrophy and fibrosis in vastus lateralis and rectus femoris muscles. Concomitant with these sarcopenic changes is an increased abundance of mitochondrial DNA deletion mutations and electron transport chain (ETC) abnormalities. In this study, we used immunohistological and histochemical approaches to define cell death pathways involved in sarcopenia. Activation of muscle cell death pathways was age-dependent with most apoptotic and necrotic muscle fibers exhibiting ETC abnormalities. Although activation of apoptosis was a prominent feature of electron transport abnormal muscle fibers, necrosis was predominant in atrophic and broken ETC-abnormal fibers. These data suggest that mitochondrial dysfunction is a major contributor to the activation of cell death processes in aged muscle fibers. The link between ETC abnormalities, apoptosis, fiber atrophy, and necrosis supports the hypothesis that mitochondrial DNA deletion mutations are causal in myofiber loss. These studies suggest a progression of events beginning with the generation and accumulation of a mtDNA deletion mutation, the concomitant development of ETC abnormalities, a subsequent triggering of apoptotic and, ultimately, necrotic events resulting in muscle fiber atrophy, breakage, and fiber loss.
authors.affiliation: Department of Biological Sciences, Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada.
authors.forename: Nashwa
authors.initials: N
authors.lastname: Cheema
authors.affiliation: Department of Agricultural, Food and Nutritional Sciences, Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada.
authors.forename: Allen
authors.initials: A
authors.lastname: Herbst
authors.affiliation: Department of Biological Sciences, Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada.
authors.forename: Debbie
authors.initials: D
authors.lastname: McKenzie
authors.affiliation: Department of Agricultural, Food and Nutritional Sciences, Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada.
authors.forename: Judd M
authors.initials: JM
authors.lastname: Aiken
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics; D004579:Electron Transport / Q000502:physiology; D008297:Male; D008928:Mitochondria / Q000201:enzymology*; D018485:Muscle Fibers, Skeletal / Q000473:pathology*; D009336:Necrosis / Q000473:pathology*; D052097:Quadriceps Muscle / Q000503:physiopathology*; D051381:Rats; D011916:Rats, Inbred F344; D055948:Sarcopenia / Q000473:pathology*; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D015415:Biomarkers; D004272:DNA, Mitochondrial
keywords: ETS abnormalities; aging; apoptosis; cell death; mitochondria; necrosis; sarcopenia; skeletal muscle