Per1/Per2–Igf2 axis–mediated circadian regulation of myogenic differentiation

Abstract

Circadian rhythms regulate cell proliferation and differentiation, but circadian control of tissue regeneration remains elusive at the molecular level. Here, we show that proper myoblast differentiation and muscle regeneration are regulated by the circadian master regulators Per1 and Per2. Depletion of Per1 or Per2 suppressed myoblast differentiation in vitro and muscle regeneration in vivo, demonstrating their nonredundant functions. Both Per1 and Per2 were required for the activation of Igf2, an autocrine promoter of myoblast differentiation, accompanied by Per-dependent recruitment of RNA polymerase II, dynamic histone modifications at the Igf2 promoter and enhancer, and the promoter–enhancer interaction. This circadian epigenetic priming created a preferred time window for initiating myoblast differentiation. Consistently, muscle regeneration was faster if initiated at night, when Per1, Per2, and Igf2 were highly expressed compared with morning. This study reveals the circadian timing as a significant factor for effective muscle cell differentiation and regeneration.

BMAL1 drives muscle repair through control of hypoxic NAD+ regeneration in satellite cells

“…We observed less repair of the damaged muscle tissue following injury at ZT4 versus ZT16 by histological quantification of muscle fiber size and size distribution at the site of injury, consistent with a recent study ( Supplemental Fig. S1 ; Katoku-Kikyo et al 2021 ). To test whether time of day control of muscle regeneration is affected by feeding and/or activity differences at the time of tissue collection, we repeated the experiment in which mice were collected at a phase opposite to the time of injury (6.5 dpi) ( Fig.…”

“…Since oxygen sensing is important for cell fate determination in a number of systems ( Ezashi et al 2005 ; Yang and Levison 2006 ; Ji et al 2009 ; Eliasson and Jönsson 2010 ), the established connection between clock and hypoxia transcription pathways poses an unexplored connection between circadian timing and cell development. Previous work has demonstrated clock regulation of myoblast differentiation and muscle repair, indicating a role for BMAL1 in the regulation of satellite cell expansion ( Andrews et al 2010 ; Zhang et al 2012 ; Chatterjee et al 2013 , 2015 ; Solanas et al 2017 ; Katoku-Kikyo et al 2021 ). However, how intrinsic MuSC clocks direct gene expression changes following injury to promote cell proliferation and differentiation is not understood.…”

“…Thus, metabolic control by environmental cues (e.g., hypoxia) is a central component of MuSC-mediated muscle regeneration, and we therefore hypothesized that clock-regulated hypoxia adaptation is central to this process. Importantly, several studies have indicated a link between circadian clock factors and the proliferation of MuSCs ( Chatterjee et al 2013 , 2015 ; Katoku-Kikyo et al 2021 ).…”

The circadian clock mediates daily bursts of cell differentiation by periodically restricting cell-differentiation commitment

“…Virtually all cells in the human body contain an intrinsic circadian clock (cell-intrinsic clock), operated by a set of core clock proteins that engage in coupled positive and negative transcriptional and translational feedback loops to generate rhythmic expression of 10 to 15% of the transcriptome ( 1 ). When components that drive the cell-intrinsic clock are genetically perturbed, cell differentiation of fat cells (adipocytes) ( 2 , 3 ), T cells ( 4 ), myoblasts ( 5 ), and embryonic stem cells ( 6 ) are defective, suggesting that the circadian clock regulates differentiation. However, it is not clear how a daily clock that oscillates perpetually can control a much slower process such as cell differentiation, which typically takes several days or even weeks.…”

Time to Train: The Involvement of the Molecular Clock in Exercise Adaptation of Skeletal Muscle

“…The knockout of CRY1/CRY2 genes, on the other hand, enhances autophagy due to a dysregulated accumulation of PER2 and the ensuing inhibition of mTORC1 ( Kalfalah et al, 2016 ). Furthermore, PER1/PER2 influence skeletal muscle regeneration in a circadian manner by activating insulin-like growth factor 2 (IGF2), which then engages the RAS/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)–AKT pathways ( Katoku-Kikyo et al, 2021 ). These observations allude to circadian control of muscle function and regeneration.…”