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

ABSTRACT: Physical 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.We 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.We 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.We 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 Ca(2+)-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.

SUBMITTER: Dyar KA

PROVIDER: S-EPMC4632177 | biostudies-other | 2015 Nov

REPOSITORIES: biostudies-other

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

Dyar Kenneth A KA Ciciliot Stefano S Tagliazucchi Guidantonio Malagoli GM Pallafacchina Giorgia G Tothova Jana J Argentini Carla C Agatea Lisa L Abraham Reimar R Ahdesmäki Miika M Forcato Mattia M Bicciato Silvio S Schiaffino Stefano S Blaauw Bert B

Molecular metabolism 20150925 11

<h4>Objective</h4>Physical 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.<h4>Methods</h4>We compared the circadian transcriptomes of two mouse hindlimb mus ...[more]

PMID: 26629406

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Project description:Hypoxia exposure is known to induce an alteration in skeletal muscle fiber-type distribution mediated by hypoxia-inducible factor (HIF)-?. The downstream pathway of HIF-? leading to fiber-type shift, however, has not been elucidated. The calcineurin pathway is one of the pathways responsible for slow muscle fiber transition. Because calcineurin pathway is activated by vascular endothelial growth factor (VEGF), one of the factors induced by HIF-1?, we hypothesized that the stabilization of HIF-1? may lead to slow muscle fiber transition via the activation of calcineurin pathway in skeletal muscles. To induce HIF-1? stabilization, we used a loss of function strategy to abrogate Prolyl hydroxylase domain protein (PHD) 2 responsible for HIF-1? hydroxylation making HIF-1? susceptible to ubiquitin dependent degradation by proteasome. The purpose of this study was therefore to examine the effect of HIF-1? stabilization in PHD2 conditional knockout mouse on skeletal muscle fiber-type transition and to elucidate the involvement of calcineurin pathway on muscle fiber-type transition.PHD2 deficiency resulted in an increased capillary density in skeletal muscles due to the induction of vascular endothelial growth factor. It also elicited an alteration of skeletal muscle phenotype toward the type I fibers in both of the soleus (35.8 % in the control mice vs. 46.7 % in the PHD2-deficient mice, p?<?0.01) and the gastrocnemius muscle (0.94 vs. 1.89 %, p?<?0.01), and the increased proportion of type I fibers appeared to correspond to the area of increased capillary density. In addition, calcineurin and nuclear factor of activated T cell (NFATc1) protein levels were increased in both the gastrocnemius and soleus muscles, suggesting that the calcineurin/NFATc1 pathway was responsible for the type I fiber transition regardless of PGC-1?, which responded minimally to PHD2 deficiency. Indeed, we found that tacrolimus (FK-506), a calcineurin inhibitor, successfully suppressed slow fiber-type formation in PHD2-deficient mice.Taken together, stabilized HIF-1? induced by PHD2 conditional knockout resulted in the transition of muscle fibers toward a slow fiber type via a calcineurin/NFATc1 signaling pathway. PHD2 conditional knockout mice may serve as a model for chronic HIF-1? stabilization as in mice exposed to low oxygen concentration.

Dataset Information

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

Publications

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

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