NFATc1 Controls Skeletal Muscle Fiber Type and Is a Negative Regulator of MyoD Activity

Abstract

SUMMARY Skeletal muscle comprises a heterogeneous population of fibers with important physiological differences. Fast fibers are glycolytic and fatigue rapidly. Slow fibers utilize oxidative metabolism and are fatigue-resistant. Muscle diseases such as sarcopenia and atrophy selectively affect fast fibers, but the molecular mechanisms regulating fiber type-specific gene expression remain incompletely understood. Here, we show that the transcription factor NFATc1 controls fiber type composition and is required for fast-to-slow fiber type switching in response to exercise in vivo. Moreover, MyoD is a crucial transcriptional effector of the fast fiber phenotype, and we show that NFATc1 inhibits MyoD-dependent fast fiber gene promoters by physically interacting with the N-terminal activation domain of MyoD and blocking recruitment of the essential transcriptional coactivator p300. These studies establish a molecular mechanism for fiber type switching through direct inhibition of MyoD to control the opposing roles of MyoD and NFATc1 in fast versus slow fiber phenotypes.

Gα13 ablation reprograms myofibers to oxidative phenotype and enhances whole-body metabolism

“…Therefore, the effect of Gα13 on NFATc1 appears to be quite distinct in skeletal muscle. This idea mirrors the reports that other isoforms except NFATc1 failed to determine fiber types in skeletal muscle (22,(38)(39)(40). We believe our research delineates the role of Gα13 signaling in the regulation of NFATc1 in energy homeostasis and elucidates the mechanism for how G protein signaling amplifies or blunts oxidative metabolism, thus providing insight into the NFATc1 regulatory pathway.…”

“…Thus, we propose that Gα13 may serve as a switch that controls the overall sensitivity of multiple receptors associated with energy metabolism. NFATc1 is the most studied regulator of myofiber type-associated gene expression (20)(21)(22). Our results reveal the physiological link between Gα13 and NFAT signaling both in vitro and in vivo.…”

“…In contrast to the activation of NFATc3 by Gα13 in fibroblasts (24), adenoviral infection of myotubes with a constitutively active Gα13 (Q229L mutant, hereafter referred to as Gα13QL) robustly inhibited the basal luciferase activity as well as that enhanced by ectopically overexpressed NFATc1 ( Figure 4D). Among NFAT proteins, NFATc1 is the predominant isoform expressed in adult skeletal muscle (22,25). So, it is conceivable that alterations in NFATc1 mainly contribute to overall NFAT activity downstream of Gα13.…”

“…Gα13 inhibits NFATc1 activity and regulates muscle oxidative capacity. Nuclear factor of activated T cells 1 (NFATc1) signaling is necessary and sufficient to transform fibers into oxidative type fibers (20)(21)(22). Therefore, we narrowed our focus to NFATc1 as a potential primary regulator of the phenotype transition resulting from Gα13 ablation.…”

Dietary thymol supplementation promotes skeletal muscle fibre type switch in longissimus dorsi of finishing pigs

“…Recent studies have shown that the expressions of MyHC I and MyHC IIa are regulated by the Ca 2+ /calcineurin/NFAT pathway (Emrani et al, ; Ravel‐Chapuis, Bélanger, Côté, Michel, & Jasmin, ) pacifically, and increase of the intracellular Ca 2+ leads to calcineurin activation and NFAT dephosphorylation consequently. The dephosphorylated NFAT will translocate to the promoter of the gene involved in oxidative metabolism in the nucleus to promote the transformation of glycolytic muscle fibres to oxidative muscle fibres in skeletal muscle (Ehlers, Celona, & Black, ; Lomonosova, Turtikova, & Shenkman, ; Pfluger et al, ). Recent studies have shown that thymol can also attenuate the oxidative stress and calcium uniporter malfunction to maintain mitochondrial function in rats (Nagoor Meeran, Jagadeesh, & Selvaraj, ) probably by regulating calcium homeostasis.…”