| Due to a multi-factorial etiology, the molecular events that contribute to aging have not been elucidated. In accordance with the mitochondrial theory of aging, the accumulation of defective mitochondrial genomes has been implicated in the physiological decline associated with aging. Sarcopenia, the age-associated loss of muscle mass and function, is the prime contributor to age-associated frailty. A major cause of sarcopenia is the loss of individual muscle fibers that leads to a permanent loss of muscle mass. The studies presented here provide support for the role of somatically-derived mitochondrial DNA deletion mutations in the age-dependent loss of skeletal muscle fibers.;To determine the impact of mitochondrial DNA deletion mutations on cellular and mitochondrial dysfunction, I measured their intracellular abundance at multiple points along the length of individual muscle fibers demonstrating that mitochondrial DNA deletion mutation accumulation precedes muscle fiber dysfunction, as characterized by electron transport chain abnormalities. These abnormalities occur when the mutation abundance surpasses a threshold of 90%, and are the result of aberrant genome accumulation, not the loss of wild-type mitochondrial genomes. These measurements link the processes of mitochondrial DNA deletion mutations, electron transport abnormalities, and fiber loss, pinning together the role of mitochondrial mutation in the etiology of muscle fiber loss, a causal event underlying sarcopenia.;Differential nuclear gene expression in response to the accumulation of deletion mutations suggested that AMP kinase activation was responsible for the accumulation and expansion of deletion mutations within individual skeletal muscle fibers. This mechanism drives mitochondrial biogenesis in response to cellular energy deficit, up-regulating mitochondrial genome replication, increasing mitochondrial DNA deletion mutation abundance. I tested this mechanism with a pharmacological activator of AMP kinase, beta-guanidinopropionic acid. Treated rats showed a 400% increase in the abundance of electron transport deficient, deletion mutation containing skeletal muscle fibers.;Here, I demonstrate that the process of mitochondrial DNA deletion mutation accumulation leads to muscle fiber dysfunction, disrupting metabolism, inducing a non-adaptive nuclear response, by driving mutation accumulation. I show how these events can lead to fiber breakage, delineating the mechanism of how mitochondrial mutation can lead to muscle fiber loss, a causal event underlying sarcopenia. |
