NFAT isoforms control activity-dependent muscle fiber type specification

Calabria, Elisa; Ciciliot, Stefano; Moretti, Irene; García, Marta; Picard, Anne; Dyar, Kenneth A.; Pallafacchina, Giorgia; Tóthová, Jana DʼAmato; Schiaffino, Stefano; Murgia, Marta

doi:10.1073/pnas.0812911106

Cited by 149 publications

(176 citation statements)

References 58 publications

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“…Calmodulin activation through binding to calcium promotes an increase in calcinueurin A activity, which has been shown to result in the exclusion of NFAT from the nucleus, to subsequently increase the activity of MEF2 and drive a slow-type fiber switch. PGC-1α has also been shown to coactivate MEF2 to promote a transition toward oxidative fiber types, a process that is thus likely to be potentiated through the PGC-1α-dependent induction of HIF2α (41)(42)(43)(44)(45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

PGC-1α regulates a HIF2α-dependent switch in skeletal muscle fiber types

Rasbach

Gupta

Ruas

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

124

105

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The coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 α (PGC-1α) coordinates a broad set of transcriptional programs that regulate the response of skeletal muscle to exercise. However, the complete transcriptional network controlled by PGC-1α has not been described. In this study, we used a qPCR-based screen of all known transcriptional components (Quanttrx) to identify transcription factors that are quantitatively regulated by PGC-1α in cultured skeletal muscle cells. This analysis identified hypoxia-inducible factor 2 α (HIF2α) as a major PGC-1α target in skeletal muscle that is positively regulated by both exercise and β-adrenergic signaling. This transcriptional regulation of HIF2α is completely dependent on the PGC-1α/ERRα complex and is further modulated by the action of SIRT1. Transcriptional profiling of HIF2α target genes in primary myotubes suggested an unexpected role for HIF2α in the regulation of muscle fiber types, specifically enhancing the expression of a slow twitch gene program. The PGC-1α–mediated switch to slow, oxidative fibers in vitro is dependent on HIF2α, and mice with a muscle-specific knockout of HIF2α increase the expression of genes and proteins characteristic of a fast-twitch fiber-type switch. These data indicate that HIF2α acts downstream of PGC-1α as a key regulator of a muscle fiber-type program and the adaptive response to exercise.

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Section: Discussionmentioning

confidence: 99%

PGC-1α regulates a HIF2α-dependent switch in skeletal muscle fiber types

Rasbach

Gupta

Ruas

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

124

105

View full text Add to dashboard Cite

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“…The coactivators PGC-1a and PGC-1b and the nuclear receptors ERRa and ERRg also drive skeletal muscle angiogenesis, at least in part via the induction of Vegfa (15)(16)(17). Changes in fiber-type composition are thought to be primarily under the control of NFAT, though they are also controlled by PGC-1a, PGC-1b, PPARd, and ERRb/ERRg (17)(18)(19)(20)(21)(22)(23)(24). Notably, many of these transcriptional regulators seem to work as a tightly knit network, crosstalking and regulating each other's expression.…”

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confidence: 99%

Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle

et al. 2015

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Skeletal muscle mitochondrial content and oxidative capacity are important determinants of muscle function and whole‐body health. Mitochondrial content and function are enhanced by endurance exercise and impaired in states or diseases where muscle function is compromised, such as myopathies, muscular dystrophies, neuromuscular diseases, and age‐related muscle atrophy. Hence, elucidating the mechanisms that control muscle mitochondrial content and oxidative function can provide new insights into states and diseases that affect muscle health. In past studies, we identified Perm1 (PPARGC1‐ and ESRR‐induced regulator, muscle 1) as a gene induced by endurance exercise in skeletal muscle, and regulating mitochondrial oxidative function in cultured myotubes. The capacity of Perm1 to regulate muscle mitochondrial content and function in vivo is not yet known. In this study, we use adeno‐associated viral (AAV) vectors to increase Perm1 expression in skeletal muscles of 4‐wk‐old mice. Compared to control vector, AAV1‐Perm1 leads to significant increases in mitochondrial content and oxidative capacity (by 40‐80%). Moreover, AAV1‐Perm1‐transduced muscles show increased capillary density and resistance to fatigue (by 33 and 31 %, respectively), without prominent changes in fiber‐type composition. These findings suggest that Perm1 selectively regulates mitochondrial biogenesis and oxidative function, and implicate Perm1 in muscle adaptations that also occur in response to endurance exercise.—Cho, Y., Hazen, B. C., Gandra, P. G., Ward, S. R., Schenk, S., Russell, A. P., Kralli, A. Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle. FASEB J. 30, 674‐687 (2016). http://www.fasebj.org

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“…These results indicate that PI3K/PKB and MAPK/ ERK pathways boost the formation of slow muscle fibers by inhibiting FoxO1. In addition, the transcription of slow and fast MyHC genes uses different combinations of nuclear factor of activated T cells (NFAT) family members, ranging from MyHC-slow, which uses all four NFAT isoforms, to MyHC IIb, which uses only NFATc4 (Calabria et al, 2009). Inhibition of the calcineurin/NFAT signaling cascade by FoxO and release of this repressive action by the PI3K/PKB pathway are important mechanisms whereby FoxO factors govern cell growth in cardiac muscles (Ni et al, 2006).…”

Section: Correlation Of Foxo1 and Myhcs In Porcine Soleus And Edl Musmentioning

confidence: 99%

Correlation of forkhead box transcription factor O1 and myosin heavy chain isoforms in porcine skeletal muscle

et al. 2014

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ABSTRACT. We examined the expression of myosin heavy chain (MyHC) isoforms and forkhead box transcription factor O1 (FoxO1) in porcine soleus and extensor digitorum longus (EDL) muscles to clarify the correlation of FoxO1 and the relative abundance of transcripts of MyHC isoforms. Soleus muscle was found to be redder than EDL muscles in pigs, and immunohistochemical fast MyHC staining showed more oxidative type I fibers compared to EDL. qRT-PCR quantification of MyHC isoforms I, IIa, IIx, and IIb showed that expression of MyHC I and MyHC IIa mRNAs was much higher, whereas expression of MyHC IIx and MyHC IIb mRNAs was much lower in porcine soleus muscle compared to EDL muscle. Expression of FoxO1 mRNA and p-FoxO1 protein was significantly more abundant in porcine soleus muscle compared to EDL muscle. The expression of phosphorylated FoxO1 (p-FoxO1) was positively correlated with the expression of MyHC I (R = 0.9747, P < 0.01) and negatively correlated with the expression of MyHC IIx (R = -0.9963, P < 0.01) and MyHC IIb (R = -0.9834, P < 0.01). Taken together, these results suggested that FoxO1 may play a pivotal role in the determination of muscle fiber type.

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NFAT isoforms control activity-dependent muscle fiber type specification

Cited by 149 publications

References 58 publications

PGC-1α regulates a HIF2α-dependent switch in skeletal muscle fiber types

PGC-1α regulates a HIF2α-dependent switch in skeletal muscle fiber types

Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle

Correlation of forkhead box transcription factor O1 and myosin heavy chain isoforms in porcine skeletal muscle

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