Cytosolic Proteostatic Adaptation to Mitochondrial Stress as a Novel Mechanism of Muscle Wasting


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Poster Number: 100


Xin Jie Chen, PhD, Xiaowen Wang, Frank Middleton, PhD, Rabi Tawil, MD


1. State University of New York Upstate Medical University, 2. SUNY Upstate Medical University, 3. SUNY Upstate Medical University, 4. University of Rochester

Mitochondrial dysfunction causes many muscle diseases and is also proposed to contribute to muscle wasting during aging. Interestingly, accumulating evidence suggest that substantial levels of bioenergetic deficiency and oxidative stress do not always by themselves cause severe muscle disorders. This raises the possibility that mitochondria may affect the physical and functional homeostasis of the skeletal muscle by additional mechanisms. Here, we show that chronic adaptations to mitochondrial protein overload and import stress cause muscle wasting. Protein overloading, together with conditions that directly and indirectly affect the protein import machinery, are known triggers of mitochondrial Precursor Over-accumulation Stress (mPOS), a newly discovered cellular stress mechanism caused by overaccumulation of mitochondrial precursors/preproteins in the cytosol (Wang and Chen, 2015, Nature 524:481-484; Liu et al., 2019, MBoC 30:1272-1284). We generated transgenic mice that have a two-fold increase in the nuclear-encoded Ant1 protein that is involved in ATP/ADP exchange on the inner mitochondrial membrane (IMM). These animals progressively lost muscle mass with age, although their lifespan was unaffected. At two years of age, the skeletal muscle of these mice was severely atrophic. The ANT1-transgenic muscles have a drastically remodeled transcriptome that appears trying to counteract mPOS, by repressing protein synthesis and stimulating proteasomal function, autophagy, lysosomal amplification and Gadd45a-signaling. These processes are all known to promote muscle wasting. Thus, chronic proteostatic adaptation to mPOS is a robust mechanism of muscle wasting. These findings may help improve the understanding of how mitochondria contribute to muscle wasting during aging. They may also have direct implications for human diseases associated with ANT1 overexpression that include facioscapulohumeral dystrophy. This study was submitted for publication ( and was supported by the NIH grants AG061204 and AG047400 to X.J.C..