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

TY - JOUR

T1 - Muscle peripheral circadian clock drives nocturnal protein degradation via raised Ror/Rev-erb balance and prevents premature sarcopenia

AU - Kelu, Jeffrey J.

AU - Hughes, Simon M.

N1 - Publisher Copyright: Copyright © 2025 the Author(s).

PY - 2025/5/13

Y1 - 2025/5/13

N2 - 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 behavioural 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 ageing-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.

AB - 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 behavioural 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 ageing-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.

KW - autophagy

KW - circadian clock

KW - mTOR

KW - muscle

KW - proteasome

UR - http://www.scopus.com/inward/record.url?scp=105004710218&partnerID=8YFLogxK

U2 - 10.1073/pnas.2422446122

DO - 10.1073/pnas.2422446122

M3 - Article

C2 - 40324095

AN - SCOPUS:105004710218

SN - 0027-8424

VL - 122

JO - Proceedings of the National Academy of Sciences USA

JF - Proceedings of the National Academy of Sciences USA

IS - 19

M1 - e2422446122

ER -