Cytosolic Adaptation to Mitochondrial Precursor Overaccumulation Stress Induces Progressive Muscle Wasting

Abstract

Mitochondrial dysfunction causes muscle wasting (or atrophy) in many diseases and probably also during aging. The underlying mechanism is unclear. Accumulating evidence suggests that substantial levels of bioenergetic deficiency and oxidative stress are insufficient by themselves to intrinsically cause muscle wasting, raising the possibility that non-bioenergetic factors may contribute to mitochondria-induced muscle wasting. In this report, we show that chronic adaptation to mitochondria-induced proteostatic stress in the cytosol induces muscle wasting. We generated transgenic mice with unbalanced mitochondrial protein loading and import, by a two-fold increase in the expression of the nuclear-encoded mitochondrial carrier protein, Ant1. We found that the ANT1-transgenic mice progressively lose muscle mass. Skeletal muscle is severely atrophic in older mice without affecting the overall lifespan. Mechanistically, Ant1 overloading induces aggresome-like structures and the expression of small heat shock proteins in the cytosol. The data support mitochondrial Precursor Overaccumulation Stress (mPOS), a recently discovered cellular stress mechanism caused by the toxic accumulation of unimported mitochondrial precursors/preproteins. Importantly, the ANT1-transgenic muscles have a drastically remodeled transcriptome that appears to be trying to counteract mPOS, by repressing protein synthesis, and by stimulating proteasomal function, autophagy and lysosomal amplification. These anti-mPOS responses collectively reduce protein content, which is known to decrease myofiber size and muscle mass. Our work therefore revealed that a subtle imbalance between mitochondrial protein load and import is sufficient to induce mPOS in vivo, and that anti-mPOS adaptation is a robust mechanism of muscle wasting. This finding may help improve the understanding of how mitochondria contribute to muscle wasting. It could have direct implications for several human diseases associated with ANT1 overexpression, including Facioscapulohumeral Dystrophy (FSHD).

Pathomechanisms and biomarkers in facioscapulohumeral muscular dystrophy: roles of DUX4 and PAX7

“…Epigenetic derepression at D4Z4, therefore, might also affect regulation of DUX4c (Ansseau et al , 2009 ). Similarly, regulation of other genes located centromeric to D4Z4 may be also be affected, with mouse models over‐expressing Frg1 (Gabellini et al , 2006 ) , Slc25a4 ( Ant1 ) (preprint: Wang et al , 2020 ) or null mutations in Fat1 (Caruso et al , 2013 ) developing muscular dystrophic phenotypes with some similarities to FSHD. Such genes may act as genetic modifiers in FSHD, affecting onset, muscle selection and/or severity (Park et al , 2018 ).…”

DUX4 Role in Normal Physiology and in FSHD Muscular Dystrophy

“…Molecularly, zinc-finger protein 555 (ZNF555) binding to a D4Z4 4qA located enhancer was shown to play a critical role in regulating ANT1 promoter activity, particularly in FSHD [ 131 ]. Intriguingly, transgenic mice with a two-fold increased ANT1 expression progressively develop muscle wasting [ 132 ], suggesting that aberrant ANT1 expression could contribute to FSHD variable penetrance.…”