The calcineurin-NFAT pathway controls activity-dependent circadian gene expression in slow skeletal muscle

Abstract

ObjectivePhysical activity and circadian rhythms are well-established determinants of human health and disease, but the relationship between muscle activity and the circadian regulation of muscle genes is a relatively new area of research. It is unknown whether muscle activity and muscle clock rhythms are coupled together, nor whether activity rhythms can drive circadian gene expression in skeletal muscle.MethodsWe compared the circadian transcriptomes of two mouse hindlimb muscles with vastly different circadian activity patterns, the continuously active slow soleus and the sporadically active fast tibialis anterior, in the presence or absence of a functional skeletal muscle clock (skeletal muscle-specific Bmal1 KO). In addition, we compared the effect of denervation on muscle circadian gene expression.ResultsWe found that different skeletal muscles exhibit major differences in their circadian transcriptomes, yet core clock gene oscillations were essentially identical in fast and slow muscles. Furthermore, denervation caused relatively minor changes in circadian expression of most core clock genes, yet major differences in expression level, phase and amplitude of many muscle circadian genes.ConclusionsWe report that activity controls the oscillation of around 15% of skeletal muscle circadian genes independently of the core muscle clock, and we have identified the Ca2+-dependent calcineurin-NFAT pathway as an important mediator of activity-dependent circadian gene expression, showing that circadian locomotor activity rhythms drive circadian rhythms of NFAT nuclear translocation and target gene expression.

Lipidomics reveals diurnal lipid oscillations in human skeletal muscle persisting in cellular myotubes cultured in vitro

“…7 A and B). Importantly, all seven mammalian elongase family members are either rhythmically expressed or their expression is affected by core clock gene alterations in peripheral mouse tissues, with Elovl1, Elovl5, and Elovl6 being circadian in mouse skeletal muscle (5,12,45). Moreover, ACSL4 was shown to be rhythmic in mouse liver, and its rhythmicity was attenuated in ClockΔ19 mutant mice (46).…”

Calcineurin signaling in the heart: The importance of time and place

“…Circadian activation of calcineurin is not unique to the heart and has also been documented in skeletal muscle [277], as evidenced by changes in Rcan1.4 transcript levels and activity of NFAT reporters. In a series of elegant experiments these investigators demonstrated that circadian activation of the calcineurin/NFAT pathway was independent of the transcriptional circadian clock mechanism, and was driven instead by muscle innervation and contractile activity.…”

Circadian regulation of muscle growth independent of locomotor activity

“…Several genes are known to regulate catabolism in muscle tissue by activating proteasomal proteolysis of sarcomeric proteins and this is thought to regulate muscle size (Bodine et al, 2001;Witt et al, 2008). Among such genes are those encoding the Muscle RING Finger (Murf) family of Tripartite Motif (Trim) proteins that have been reported to undergo circadian changes in mRNA level in muscle (Amaral and Johnston, 2012;Dyar et al, 2018Dyar et al, , 2015McCarthy et al, 2007). Analysis of murf1/trim63a and murf2/trim55b mRNA levels in 3-5 dpf larvae by qRT-PCR suggested that these genes undergo circadian cycling, such that they peak in every dark phase at ZT15 (Fig.…”

“…Previous studies, generally performed on adult rodent limb muscle, indicated that protein synthesis, as reflected by either p70S6K and ERK1/2 phosphorylation (Chang et al, 2016) or puromycin incorporation (Dyar et al, 2018), display a day/night variation in skeletal muscle. In addition, the expression of atrogenes, such as atrogin1 and murf1, were shown to undergo rhythmic circadian changes in skeletal muscle (Dyar et al, 2018(Dyar et al, , 2015McCarthy et al, 2007;Perrin et al, 2018). Some of these circadian differences were shown to be abolished by loss-of-function of core clock genes (Dyar et al, 2018(Dyar et al, , 2015, indicating the critical requirement of the molecular clock in regulating muscle metabolism.…”