Calcineurin controls nerve activity-dependent specification of slow skeletal muscle fibers but not muscle growth

Serrano, Antonio L.; Murgia, Marta; Pallafacchina, Giorgia; Calabria, Elisa; Coniglio, Patrizia; Lømo, Terje; Schiaffino, Stefano

doi:10.1073/pnas.231148598

Cited by 236 publications

(262 citation statements)

References 39 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

104

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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

104

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“…Thr phosphatase activated by Ca 2ϩ -calmodulin, is also known to be involved in the maintenance of the slow muscle fiberspecific gene expression, and suppression of its activity causes a transformation from slow to fast fiber type-specific gene expression (38,39). We identified SURE and FIRE motifs in the pColQ-1 and pColQ-1a promoters, respectively.…”

Section: Fig 8 Mutation Of the Nfat Motif Of Pcolq-1 Blocks Its Fibmentioning

confidence: 96%

“…NFAT exists as four isoforms: NFATc, NFATp, NFAT4/x/ c3, and NFAT3 (24,38,39); skeletal muscles express NFATc, NFATp, and NFAT4/x/c3 (40). A search in pColQ-1 revealed a possible NFAT binding site within the SURE motif (see Figs.…”

Section: Two Distinct Promoters Drive the Differential Expression Ofmentioning

confidence: 99%

Transcriptional Regulation of Acetylcholinesterase-associated Collagen ColQ

Lee

Choi

Ting

et al. 2004

Journal of Biological Chemistry

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The presence of a collagenous protein (ColQ) characterizes the collagen-tailed forms of acetylcholinesterase and butyrylcholinesterase at vertebrate neuromuscular junctions which is tethered in the synaptic basal lamina. ColQ subunits, differing mostly by their signal sequences, are encoded by transcripts ColQ-1 and ColQ-1a, which are differentially expressed in slow and fast twitch muscles in mammals. Two distinct promoters, pColQ-1 and pColQ-1a, were isolated from the upstream sequences of human COLQ gene; they showed musclespecific expression and were activated by myogenic transcriptional elements in cultured myotubes. After in vivo DNA transfection, pColQ-1 showed strong activity in slow twitch muscle (e.g. soleus), whereas pColQ-1a was preferably expressed in fast twitch muscle (e.g. tibialis). Mutation analysis of the ColQ promoters suggested that the muscle fiber type-specific expression pattern of ColQ transcripts were regulated by a slow upsteam regulatory element (SURE) and a fast intronic regulatory element (FIRE). These regulatory elements were responsive to a calcium ionophore and to calcineurin inhibition by cyclosporine A. The slow fiber type-specific expression of ColQ-1 was abolished by the mutation of an NFAT element in pColQ-1. Moreover, both the ColQ promoters contained N-box element that was responsible for the synapse-specific expression of ColQ transcripts. These results explain the specific expression patterns of collagen-tailed acetylcholinesterase in slow and fast muscle fibers.

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“…FK506 has distinct molecular structure as compared to CsA, however it binds to the same surface of calcineurin (Huai et al., 2002) and efficiently inhibits calcineurin with 100-fold lower concentration as compared to CsA (Liu et al, 1991). The doses of CsA and FK506 utilized in the present work in vivo (20 and 2 mg/kg/day b.w., respectively) and in vitro (10 − 6 M) have been previously studied and are able to significantly reduce calcineurin activity (∼ 60%) (Lai et al, 1998;Dunn et al, 1999;Friday et al, 2000;Dunn et al, 2001;Serrano et al, 2001;Miyabara et al, 2005). Calcineurin inhibition by CsA (Fig.…”

Section: Discussionmentioning

confidence: 99%

Effect of calcineurin inhibitors on myotoxic activity of crotoxin and Bothrops asper phospholipase A2 myotoxins in vivo and in vitro

Miyabara¹,

Baptista²,

Lomonte³

et al. 2006

Comparative Biochemistry and Physiology Part C: Toxicology &

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Previous studies have shown that calcineurin activity plays a critical role in the myotoxic activity induced by crotoxin (CTX), a group II phospholipase A 2 (PLA 2 ) with neurotoxic and myotoxic actions. In order to address whether calcineurin is also important for the activity of nonneurotoxic group II PLA 2 myotoxins we have compared the effects of calcineurin inhibition on the myotoxic capacity of CTX and the nonneurotoxic PLA 2 s, myotoxin II (Mt II) and myotoxin III (Mt III) from Bothrops asper venom. Rats were treated with cyclosporin A (CsA) or FK506, calcineurin inhibitors, and received an intramuscular injection of either CTX, Mt II or Mt III into the tibialis anterior. Animals were killed 24 h after injection of toxins. Tibialis anterior was removed and stored in liquid nitrogen. Myofibers in culture were also treated with CsA or FK506 and exposed to CTX, Mt II and Mt III. It was observed that, in contrast to CTX, CsA and FK506 do not attenuate myotoxic effects induced by both Mt II and Mt III in vivo and in vitro. The results of the present study suggest that calcineurin is not essential for the myotoxic activity of Mt II and Mt III, indicating that distinct intracellular pathways might be involved in myonecrosis induced by neurotoxic CTX and non-neurotoxic Bothrops sp. PLA 2 myotoxins. Alternatively, calcineurin dependent fast fiber type shift might render the muscle resistant to the action of CTX, without affecting its susceptibility to Bothrops sp. myotoxins.

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Calcineurin controls nerve activity-dependent specification of slow skeletal muscle fibers but not muscle growth

Cited by 236 publications

References 39 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

Transcriptional Regulation of Acetylcholinesterase-associated Collagen ColQ

Effect of calcineurin inhibitors on myotoxic activity of crotoxin and Bothrops asper phospholipase A2 myotoxins in vivo and in vitro

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