Distinct roles of NFATc1 and NFATc4 in human primary myoblast differentiation and in the maintenance of reserve cells

Abstract

Ca signaling plays a key role during human myoblast differentiation. Among Ca-sensitive pathways, calcineurin is essential for myoblast differentiation and muscle regeneration. Nuclear factor of activated T-cell (NFAT) transcription factors are the major calcineurin targets. We investigated the expression and the role of each NFAT gene during human primary myoblast differentiation. We found that three NFAT isoforms are present, NFATc1, NFATc3 and NFATc4. Importantly, while their mRNA expression increases during differentiation, NFATc1 is more highly expressed in myotubes, whilst NFATc4 is specifically maintained in reserve cells. NFATc3 is present in both cell types, although no specific role during myoblast differentiation was observed. Knockdown of either NFATc1 or NFATc4 affects the differentiation process similarly, by decreasing the expression of late differentiation markers, but impairs myotube formation differently. Whereas NFATc1 knockdown strongly reduced the number and the surface area of myotubes, NFATc4 knockdown increased the surface area of myotubes and reduced the pool of reserve cells. We conclude that NFAT genes have specific roles in myotube formation and in the maintenance of the reserve cell pool during human postnatal myogenesis.

Magnetic fields modulate metabolism and gut microbiome in correlation with Pgc‐1α expression: Follow‐up to an in vitro magnetic mitohormetic study

“…Notably, statistical significance was observed for the Solei genes, Sirt1 , Mef2c , and Vegf‐a , in the PEMF‐treated alone (–E/+P) cohort relative to controls (–E/–P), whereas exercised mice, with (+E/+P) or without (+E/–P) PEMF treatment, were not statistically different from sham controls (–E/–P). MEF2C promotes PGC‐1α expression 23,46,55‐57 and correlates with NFATC1 expression pattern 36,58 that precedes and predicts oxidative muscle development 59 . SIRT1 stimulates PGC‐1α expression, upstream of mitochondriogenesis and metabolic balance 11 .…”

Neurogranin is expressed in mammalian skeletal muscle and inhibits calcineurin signaling and myoblast fusion

“…3, A and B). Myogenin is a common marker of myoblast differentiation that is regulated by the calcineurin-NFAT axis (2,42). Other indicators of differentiation were also increased in Ng siRNA cells.…”

Ezrin regulated myoblast differentiation/fusion and muscle fiber specialization through PKA-NFAT-MyoD/MEF2csignalling pathway

“…Moreover, NFATs activities are frequently regulated by the PKAcalcineurinsignalling pathway during cell differentiation 33,34,35,36 . Indeed, NFATc2 primarily controlled myoblast recruitment and myoblast fusion 37,38,39,40 . Similarly, we found that the inhibitory effect of myoblast fusion by knockdown of Ezrin could be restored by the overexpression of NFATc2, but not NFATc1.…”

“…Previous reports have shown that NFATc2 could perform speci c role in MyHC-2a and MyHC-2X expression with synergistic effect of MyoD while NFATc1 promoted MyHC-1 expression through inhibiting MyoD signaling 37,40 . More, NFATc4 has shown the inhibitory role in myoblast fusion 38 , and appears to mostly contribute to fast muscle ber formation, especially MyHC-2b 30 . The overexpression of NFATc4 affects the differentiation process by decreasing the expression of late differentiation markers, including MEF2c, and impairs myotube formation 30,38 .…”

“…More, NFATc4 has shown the inhibitory role in myoblast fusion 38 , and appears to mostly contribute to fast muscle ber formation, especially MyHC-2b 30 . The overexpression of NFATc4 affects the differentiation process by decreasing the expression of late differentiation markers, including MEF2c, and impairs myotube formation 30,38 . We found that these similar effects mediated by the knockdown of Ezrin could be reversed by knockdown of NFATc4.…”