The Role of Apoptosis and Necrosis in Age-Dependent Enzymatic Mitochondrial Abnormalities in Individual Skeletal Muscle Fibers

  • Author / Creator
    Cheema, Nashwa J.
  • 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.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Department of Biological Sciences
  • Specialization
    • Physiology, Cell and Developmental Biology
  • Supervisor / co-supervisor and their department(s)
    • Judd Aiken (Department of Agricultural, Food and Nutritional Sciences)
    • Debbie McKenzie (Department of Biological Sciences)
  • Examining committee members and their departments
    • Satyabrata Kar (Department of Psychiatry)
    • Frank Nargang (Department of Biological Sciences)