Muscle peripheral circadian clock drives nocturnal protein degradation via raised Ror/Rev-erb balance and prevents premature sarcopenia

Abstract

How central and peripheral circadian clocks regulate protein metabolism and affect tissue mass homeostasis has been unclear. Circadian shifts in the balance between anabolism and catabolism control muscle growth rate in young zebrafish independent of behavioral cycles. Here, we show that the ubiquitin–proteasome system (UPS) and autophagy, which mediate muscle protein degradation, are each upregulated at night under the control of the muscle peripheral clock. Perturbation of the muscle transcriptional molecular clock disrupts nocturnal proteolysis, increases muscle growth measured over 12 h, and compromises muscle function. Mechanistically, the shifting circadian balance of Ror and Rev-erb regulates nocturnal UPS, autophagy, and muscle growth through altered TORC1 activity. Although environmental zeitgebers initially mitigate defects, lifelong muscle clock inhibition reduces muscle size and growth rate, accelerating aging-related loss of muscle mass and function. Circadian misalignment such as shift work, sleep deprivation, or dementia may thus unsettle muscle proteostasis, contributing to muscle wasting and sarcopenia.