Mitochondrial DNA Deletion Mutations: A Molecular Cause of Age-Induced Skeletal Muscle Fiber Dysfunction and Fiber...

This chapter describes a molecular basis for age-induced muscle fiber loss involving the mammalian mitochondrial genome (mtDNA). Early studies of human mitochondrial myopathies, which display many phenotypes associated with muscle aging, led to the search for and subsequent discovery of similar genetic and histopathological changes in aging skeletal muscle. A diverse spectrum of mtDNA deletion mutations increase in abundance with age and clonally accumulate to high abundance within individual cells. Deletion accumulation results in a focal loss of electron transport and oxidative phosphorylation. These metabolic derangements activate apoptosis, leading to necrosis, fiber splitting, and eventual fiber loss. We have identified a number of interventions that are capable of modulating mtDNA deletion mutation frequency and the abundance of electron transport chain deficient fibers. Interestingly, in each case, the genetic and histological measures of mtDNA quality predict the lifespan effects of these interventions. We highlight the value of incorporating a geroscience view into the study of sarcopenia. The sequence of events from the deletion mutation of a single mtDNA molecule to muscle fiber death is not limited to skeletal muscle and has been observed in most other aging tissues, where these events likely contribute to cell loss.