Proteasome-dependent Activation of Mammalian Target of Rapamycin Complex 1 (mTORC1) Is Essential for Autophagy Suppression and Muscle Remodeling Following Denervation (2012)

Drastic protein degradation occurs during muscle atrophy induced by denervation, fasting, immobility, and various systemic diseases. Although the ubiquitin-proteasome system is highly up-regulated in denervated muscles, the involvement of autophagy and protein synthesis has been controversial. Here, we report that autophagy is rather suppressed in denervated muscles even under autophagy-inducible starvation conditions. This is due to a constitutive activation of mammalian target of rapamycin complex 1 (mTORC1). We further reveal that denervation-induced mTORC1 activation is dependent on the proteasome, which is likely mediated by amino acids generated from proteasomal degradation. Protein synthesis and ribosome biogenesis are paradoxically increased in denervated muscles in an mTORC1-dependent manner, and mTORC1 activation plays an anabolic role against denervation-induced muscle atrophy. These results suggest that denervation induces not only muscle degradation but also adaptive muscle response in a proteasome- and mTORC1-dependent manner.Background: The overall protein metabolism during denervation atrophy remains unclear.Results: Autophagy is suppressed, whereas ribosome and protein synthesis are up-regulated in denervated muscles by proteasome-dependent activation of mTORC1.Conclusion: Denervation does not simply induce muscle degradation but also promotes proteasome- and mTORC1-dependent muscle remodeling.Significance: This information is beneficial for understanding the pathophysiology of other types of muscle atrophy. Drastic protein degradation occurs during muscle atrophy induced by denervation, fasting, immobility, and various systemic diseases. Although the ubiquitin-proteasome system is highly up-regulated in denervated muscles, the involvement of autophagy and protein synthesis has been controversial. Here, we report that autophagy is rather suppressed in denervated muscles even under autophagy-inducible starvation conditions. This is due to a constitutive activation of mammalian target of rapamycin complex 1 (mTORC1). We further reveal that denervation-induced mTORC1 activation is dependent on the proteasome, which is likely mediated by amino acids generated from proteasomal degradation. Protein synthesis and ribosome biogenesis are paradoxically increased in denervated muscles in an mTORC1-dependent manner, and mTORC1 activation plays an anabolic role against denervation-induced muscle atrophy. These results suggest that denervation induces not only muscle degradation but also adaptive muscle response in a proteasome- and mTORC1-dependent manner. Background: The overall protein metabolism during denervation atrophy remains unclear. Results: Autophagy is suppressed, whereas ribosome and protein synthesis are up-regulated in denervated muscles by proteasome-dependent activation of mTORC1. Conclusion: Denervation does not simply induce muscle degradation but also promotes proteasome- and mTORC1-dependent muscle remodeling. Significance: This information is beneficial for understanding the pathophysiology of other types of muscle atrophy. Proteasome-dependent activation of mammalian target of rapamycin complex 1 (mTORC1) is essential for autophagy suppression and muscle remodeling following denervation.Journal of Biological ChemistryVol. 288Issue 19PreviewVOLUME 288 (2013) PAGES 1125–1134 Full-Text PDF Open Access