Mechanism of Mitochondria-Induced Muscle Atrophy During Aging

Abstract

Mitochondrial dysfunction is strongly associated with aging-related degenerative diseases including muscle atrophy. However, whether bioenergetic defects are the sole drivers of mitochondria-induced muscle atrophy remains unknown. The Chen lab discovered that various forms of mitochondrial damage can disrupt protein import, leading to the toxic accumulation of unimported mitochondrial precursors in the cytosol. This causes a stress termed mitochondrial Precursor Over-accumulation Stress (mPOS). A mouse model of mPOS was developed in which the mitochondrial inner membrane protein, ANT1, was overexpressed to saturate the protein import machinery. Ant1Tg/+ mice were found to have a severe muscle wasting phenotype. The overarching goal of this dissertation is to investigate the mechanism by which mPOS drives muscle wasting and its implications for normative muscle aging. The findings presented in this thesis led to three conclusions.

First, we identified a novel mitochondria-to-lysosomal proteostatic axis through which mPOS induces lysosomal damage. Lysosomal damage subsequently causes the release proteolytic enzymes, which leads to excessive protein degradation and subsequent progressive muscle atrophy. Importantly, we found that this pathway operates independently of mitochondrial respiratory complex activity and reactive oxygen species (ROS) production. Second, we demonstrated the presence of mPOS in physiologically aged muscle. Sarcopenic muscle exhibited phenotypes similar to those found in Ant1Tg/+ mice, evidenced by overlapping transcriptional and proteomic profiles, and lysosomal damage. These findings indicate that mitochondria-induced changes to autophagic activity may play a central role in the pathogenesis of sarcopenia. However, considering the overall protein content of muscle is elevated during aging, we propose that reduced protein quality, rather than absolute protein content, drives sarcopenia. We therefore termed this phenomenon Muscle Atrophy Independent of Protein Content (MAIPC).

Finally, we explored additional cellular factors that affect proteostasis and muscle mass maintenance. We found that the GCN2 kinase, a well-established activator of the Integrated Stress Response (ISR), plays a role in protecting myofibers from mPOS-induced stress and muscle wasting in Ant1Tg/+ muscle. Interestingly, we found that this effect is ISR-independent.

The data presented in this dissertation provide valuable insights into the mechanistic role of mitochondrial dysfunction in both normative aging and chronic muscle wasting conditions. Our findings conclude that mitochondria-induced muscle atrophy is induced by mechanisms that extend beyond bioenergetic defects. By characterizing these alternative pathways, this work opens new avenues for therapeutic strategies targeting mitochondrial stress in chronic muscle wasting conditions.