Cytosolic adaptation to mitochondria-induced proteostatic stress causes progressive muscle wasting

Mitochondrial dysfunction causes muscle wasting in many diseases and probably also during aging. The underflying mechanism is poorly understood. We generated transgenic mice with unbalanced mitochondria! protein loading and import, by moderately overexpressing the nuclear-encoded adenine nucleotide translocase, Ant1. We found that these mice progressively lose skeletal muscle. Ant1-overloading reduces mitochondrial respiration. Interestingly, it also induces small heat shock proteins and aggresome-like structures in the cytosol, suggesting increased proteostatic burden due to accumulation of unimported mitochondrial preproteins. The transcriptome of Ant1-transgenic muscles is drastically remodeled to counteract proteostatic stress, by repressing protein synthesis and promoting proteasomal function, autophagy, and lysosomal amplification. These proteostatic adaptations collectively reduce protein content thereby reducing myofiber size and muscle mass. Thus, muscle wasting can occur as a trade-off of adaptation to mitochondria-induced proteostatic stress. This finding could have implications for understanding the mechanism of muscle wasting, especially in diseases associated with Ant1 overexpression, including facioscapulohumeral dystrophy.

Automated summary

This study explored the mechanism of muscle wasting caused by mitochondrial dysfunction. Through transgenic mice experiments, it was found that overexpression of the nuclear-encoded adenine nucleotide translocase, Ant1, led to reduced mitochondrial respiration and induced heat shock proteins and aggresome-like structures in the cytosol. The transcription of Ant1-transgenic muscles was remodeled to counteract proteostatic stress, resulting in reduced myofiber size and muscle mass.