Cytosolic Proteostatic Adaptation to Mitochondrial Stress Causes Progressive Muscle Wasting

ABSTRACT

Muscle wasting (or atrophy), defined by reduced myofiber size and muscle strength, occurs in primary neuromuscular diseases and during aging. The progressive loss of muscle mass with aging is known as sarcopenia, and affects 35.4% and 75.5% of women and men over 60 years of age, respectively ¹. Mitochondrial dysfunction has been proposed to contribute to progressive muscle wasting ^{2, 3}. Interestingly, substantial levels of bioenergetic deficiency and oxidative stress seem to be insufficient by themselves to intrinsically cause muscle wasting during aging⁴. This raises the possibility that mitochondria may affect muscle mass by additional mechanisms. Here, we show that chronic adaptations to mitochondrial protein overload 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 toxic accumulation of precursor proteins in the cytosol ^5–7. Our evidence was obtained from transgenic mice that were generated to 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 ^{8, 9}. 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^10–12.