Cry2 Is Critical for Circadian Regulation of Myogenic Differentiation by Bclaf1-Mediated mRNA Stabilization of Cyclin D1 and Tmem176b

Abstract

SUMMARY Circadian rhythms regulate cell proliferation and differentiation; however, little is known about their roles in myogenic differentiation. Our synchronized differentiation studies demonstrate that myoblast proliferation and subsequent myotube formation by cell fusion occur in circadian manners. We found that one of the core regulators of circadian rhythms, Cry2, but not Cry1, is critical for the circadian patterns of these two critical steps in myogenic differentiation. This is achieved through the specific interaction between Cry2 and Bclaf1, which stabilizes mRNAs encoding cyclin D1, a G1/S phase transition regulator, and Tmem176b, a transmembrane regulator for myogenic cell fusion. Myoblasts lacking Cry2 display premature cell cycle exit and form short myotubes because of inefficient cell fusion. Consistently, muscle regeneration is impaired in Cry2−/− mice. Bclaf1 knockdown recapitulated the phenotypes of Cry2 knockdown: early cell cycle exit and inefficient cell fusion. This study uncovers a post-transcriptional regulation of myogenic differentiation by circadian rhythms.

Single cell analysis of adult mouse skeletal muscle stem cells in homeostatic and regenerative conditions

“…Indeed, metabolites generated by different metabolic pathways regulate the activity of chromatin-modifying enzymes known to control different aspects of MuSC biology (McKinnell et al, 2008;Juan et al, 2011;Kawabe et al, 2012;Liu et al, 2013;Ryall et al, 2015b;Boonsanay et al, 2016;Faralli et al, 2016;Scionti et al, 2017;Das et al, 2017;Tosic et al, 2018;Puri and Mercola, 2012). For instance, the oscillation of intermediary metabolites of the NAD biosynthetic pathways may be relevant for circadian gene expression in MuSCs and skeletal muscle (Nakahata et al, 2009;Ryall et al, 2015b;Solanas et al, 2017;Andrews et al, 2010;Lowe et al, 2018). Lastly, perturbations of specific metabolic pathways induce state changes in MuSCs (Ryall et al, 2015b;Pala et al, 2018), revealing a central role of metabolism in regulating cell state transitions.…”

Cryptochromes Mediate Intrinsic Photomechanical Transduction in Avian Iris and Somatic Striated Muscle

“…While scant clues are available, knowing if light generates CRY-mediated Ca 2+ mobilization in striated muscle from other species and/or in other cell types may provide useful insights. Given the developmentally transient PMT in developing Gallus iris shown here and elsewhere to be CRY-mediated (Meriney and Pilar, 1987;Pilar et al, 1987;Tu, 2004) some crossover functions seem likely since CRY2 and CRY associated redox rhythms have recently been implicated in myogenesis (Grande et al, 2003;Bothwell and Gillette, 2018;Lowe et al, 2018). In this regard it would be useful to know if altering CRY expression and light exposure in myoblasts influences their subsequent differentiation.…”

Promotion of Myoblast Differentiation by Fkbp5 via Cdk4 Isomerization

“…This was performed as described previously ( Lowe et al, 2018 ). The proteins obtained with immunoprecipitation were separated with a Criterion 8%–16% Tris-HCl gradient gel (Bio-Rad Laboratories, 3450038).…”