mTORC1 hyperactivation in skeletal muscle produces early‐onset myopathy associated with autophagy dysregulation

By upregulating protein anabolism, mTORC1 maintains muscle mass and growth. However, mTORC1 upregulation is also known to promote muscle aging and produce age‐associated myopathy. Whether mTORC1 activation is sufficient to produce myopathy or indirectly promotes it by accelerating tissue aging is elusive. Here we examined the effect of muscular mTORC1 hyperactivation, produced by concomitant deletion of Tsc1 and Depdc5 (MCK‐TD). MCK‐TD mice produced severe myopathy, associated with loss of skeletal muscle mass and force, as well as cardiac muscle hypertrophy and bradypnea. The pathologies were manifested at eight weeks of age, leading to a highly penetrant fatality at around twelve weeks of age. Transcriptome analysis indicates that both proteasomal and autophagic pathways were highly upregulated in MCK‐TD skeletal muscle, in addition to inflammation, oxidative stress, and DNA damage signaling pathways. Upon mTORC1 hyperactivation, autophagosome levels were unexpectedly increased with AMPK and ULK1 upregulation. Despite the strong upregulation of autolysosomal capacities, autophagosomal‐lysosomal fusion was not efficient, leading to prominent accumulation of undegraded autophagosomes and autophagy substrates. Administration of a superoxide scavenger tempol normalized most of these molecular pathologies and subsequently restored muscle histology and force generation. These results collectively indicate that mTORC1 hyperactivation is sufficient to produce early‐onset myopathy in mice. Mitochondrial oxidative stress is likely the major output of how mTORC1 hyperactivation can acutely damage the muscle tissue and dysregulate autophagic and proteasomal signaling pathways.