The Role of Apoptosis and Necrosis in Age-Dependent Enzymatic Mitochondrial Abnormalities in Individual Skeletal Muscle Fibers Open Access
- Other title
ETC abnormalities, sarcopenia, apoptosis, necrosis, fiber loss, muscle aging, myofiber cell death
- Type of item
- Degree grantor
University of Alberta
- Author or creator
Cheema, Nashwa J.
- Supervisor and department
Judd Aiken (Department of Agricultural, Food and Nutritional Sciences)
Debbie McKenzie (Department of Biological Sciences)
- Examining committee member and department
Frank Nargang (Department of Biological Sciences)
Satyabrata Kar (Department of Psychiatry)
Department of Biological Sciences
Physiology, Cell and Developmental Biology
- Date accepted
- Graduation date
Doctor of Philosophy
- Degree level
Aging is associated with the functional decline of cells, tissues and organs affecting the lifespan of all organisms. Age-associated changes to the skeletal muscle such as decline in muscle mass and function is termed as sarcopenia. Sarcopenia results from fiber atrophy and loss of myofibers. We have previously characterized sarcopenia in Fischer Brown Norway (FBN) rats, documenting age-dependent declines in muscle mass and fiber number in quadriceps muscles. The sarcopenic changes in the muscle is concomitant with increased abundance of mitochondrial DNA deletion mutations and electron transport chain abnormalities. We have previously established the physiological impact of mtDNA deletions in aged fibers in rats, monkeys and humans. mtDNA deletions accumulate in aged myofibers via mitochondrial biogenesis to a level of 95-98% of mitochondrial genomes in the cell. The deletions in the mitochondrial genome span the major arc region of the genome and are 2-10 kbp in length which results in the disruption of protein complexes in the electron transport chain (ETC). Fibers with an abnormal ETC, do not have a functional complex IV, cytochrome c oxidase (COX) and have a hyperactive complex II, succinate dehydrogenase (SDH). ETC abnormal fibers are more prone to intra-fiber atrophy and fiber breakage suggesting that they may play a significant role in fiber loss through unknown molecular pathways. 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 electron transport chain 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 electron transport chain abnormalities, apoptosis, fiber atrophy and necrosis supports the hypothesis that mitochondrial DNA deletion mutations are causal in myofiber loss. To test the causal relationship of ETC abnormal fibers in myofiber loss in aged tissue, we pharmacologically induced ETC abnormal fibers via latent mtDNA deletion accumulation. We observed a 1,200% increase in electron transport chain abnormal muscle fibers, an 18% decrease in muscle fiber number, 22% loss of muscle mass, increased deposition of fibrosis and increased abundance of apoptotic myofibers. 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. These data affirm the hypothesized role for mitochondrial dysfunction in the etiology of muscle fiber loss at old age.
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- Citation for previous publication
Cheema, N., Herbst, A., McKenzie, D. and Aiken, J.M. 2015. Apoptosis and necrosis mediate skeletal muscle fiber loss in age-induced mitochondrial enzymatic abnormalities. Aging Cell. 14:1085-1093.Herbst, A., Wanagat, J., Cheema,N., Widjaja, K., McKenzie, D. and Aiken, J.M. 2016. Latent mitochondrial DNA deletion mutations drive muscle fiber loss at old age. Aging Cell. 15:1132-1139.
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