A Calcineurin-NFATc3-Dependent Pathway Regulates Skeletal Muscle Differentiation and Slow Myosin Heavy-Chain Expression

Delling, Ulrike; Turečková, Jolana; Lim, Hae W.; Windt, León J. De; Rotwein, Peter; Molkentin, Jeffery D

doi:10.1128/.20.17.6600-6611.2000

Cited by 67 publications

(92 citation statements)

References 32 publications

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“…durance training can cause dramatic changes in muscle fiber type composition (24). Furthermore, constitutively active MAP kinase kinase 6, an upstream kinase of p38, is reported to promote fast MyHC expression in the presence of forced MyoD expression (38). Meissner (26) also reported that p38 MAPK can regulate MyHC IIx promoter activity yet has little effect on fast MyHC IIa promoter activity (39).…”

Section: Discussionmentioning

confidence: 99%

Modulation of skeletal muscle fiber type by mitogen‐activated protein kinase signaling

Shi¹,

Scheffler²,

Pleitner³

et al. 2008

FASEB j.

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Skeletal muscle is composed of diverse fiber types, yet the underlying molecular mechanisms responsible for this diversification remain unclear. Herein, we report that the extracellular signal-regulated kinase (ERK) 1/2 pathway, but not p38 or c-Jun NH(2)-terminal kinase (JNK), is preferentially activated in fast-twitch muscles. Pharmacological blocking of ERK1/2 pathway increased slow-twitch fiber type-specific reporter activity and repressed those associated with the fast-twitch fiber phenotype in vitro. Overexpression of a constitutively active ERK2 had an opposite effect. Inhibition of ERK signaling in cultured myotubes increased slow-twitch fiber-specific protein accumulation while repressing those characteristic of fast-twitch fibers. Overexpression of MAP kinase phosphatase-1 (MKP1) in mouse and rat muscle fibers containing almost exclusively type IIb or IIx fast myosin heavy chain (MyHC) isoforms induced de novo synthesis of the slower, more oxidative type IIa and I MyHCs in a time-dependent manner. Conversion to the slower phenotype was confirmed by up-regulation of slow reporter gene activity and down-regulation of fast reporter activities in response to forced MKP1 expression in vivo. In addition, activation of ERK2 signaling induced up-regulation of fast-twitch fiber program in soleus. These data suggest that the MAPK signaling, most likely the ERK1/2 pathway, is necessary to preserve the fast-twitch fiber phenotype with a concomitant repression of slow-twitch fiber program.

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Section: Discussionmentioning

confidence: 99%

Modulation of skeletal muscle fiber type by mitogen‐activated protein kinase signaling

Shi¹,

Scheffler²,

Pleitner³

et al. 2008

FASEB j.

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“…Recent reports implicating the calcineurin-NFAT pathway during myotube differentiation and fiber type switching encountered difficulties in directly demonstrating NFAT translocation (Delling et al 2000) or the necessity of NFAT-mediated gene expression during these processes (Friday et al 2000;Swoap et al 2000). Factors such as NFAT shuttling dynamics, or the nerve-induced pattern of contractile activity, driving changes in the intracellular Ca 2+ concentration, may be key to the link between calcineurin and NFAT in these studies.…”

Section: Physiological Relevance Of Ache Activation By Nfatmentioning

confidence: 99%

NFATc1 activates the acetylcholinesterase promoter in rat muscle

Cohen

Randall

2004

Journal of Neurochemistry

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Nuclear factor of activated T-cells (NFAT) plays a role in the response of muscle to chronic contractile activity that can result in fiber type switching and hypertrophy. These effects are due in part to activation of target genes following Ca 2+ -mediated nuclear translocation of NFAT. Acetylcholinesterase (AChE), a component of the neuromuscular junction, is regulated by chronic muscle and nerve activity through changes in intracellular Ca 2+, suggesting that the Ache gene may be a potential downstream target of NFAT signaling. To determine whether elements of the Ache promoter are modulated by NFAT, we transiently co-expressed reporter constructs driven by fragments of the Ache promoter with an NFATc1 that is constitutively translocated to the nucleus [NFATc1(S fi A)] in rat muscle cultures. NFATc1 potentiated reporter activity when co-transfected with constructs containing Ache genomic elements from )1280 to )490 bp upstream of transcription initiation. Electrophoretic mobility shift assays demonstrated strong binding to a potential NFAT element at )793 bp and weaker binding to one at )678 bp. Co-transfection of promoter fragments, containing the binding sites at )793 and at )678 bp, with NFATc1(S fi A) potentiated reporter activity, supporting sites of interaction with NFAT. Our data suggests a role for NFAT as a modulator of Ache gene transcription. Keywords: acetylcholinesterase, muscle culture, nuclear factor of activated T-cells, promoter, transcription factor. Acetylcholinesterase (AChE, EC 3.7.1.1) is a serine hydrolase produced by skeletal muscle required for termination of neurotransmission. AChE activity is altered by physiological changes such as muscle contractile pattern, fiber type, and innervation. One common element underlying these changes is the modulation of intracellular Ca 2+ . Elevation of intracellular Ca 2+ increases Ache transcript levels during differentiation of myoblasts to myotubes (Fuentes and Taylor 1993). One pathway of Ca 2+ signaling during myogenesis is through the activation of the Ca 2+ -dependent phosphatase, calcineurin, ultimately resulting in an increase in the stability of mRNA encoding AChE (Luo et al. 1999). Ca 2+ signaling also has been implicated in the regulation of AChE during fast-to-slow fiber type switching. AChE activity is lower in slow-twitch than in fast-twitch muscle (Bacou et al. 1982;Lomo et al. 1985;Fernandez and Donoso 1988). AChE transcripts are more abundant in fast-twitch muscle but are reduced after chronic low-frequency stimulation that results in a fast-to-slow fiber type conversion (Sketelj et al. 1998). AChE transcripts are also increased in skeletal muscle hypertrophy resulting from chronic exercise (Sveistrup et al. 1995). These studies indicate that Ca 2+ -dependent signaling pathways regulate AChE in muscle and suggest that the Ache gene may be a downstream target of calcineurin signaling. One downstream target of calcineurin is NFAT (nuclear factor of activated T cells; reviewed in Rao et al. 1997 Abbreviations used: AChE, acety...

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“…(NFATc1) and nuclear translocation of nuclear activated T-cell c3 (NFATc3) (Abbott et al, 1998;Delling et al, 2000) which leads to the transcription of NFAT-dependent genes, including multiple hypertrophic marker genes such as GATA binding protein 2 (GATA-2) ( Fig. 5) (Allen & Leinwand, 2002;Delling et al, 2000;Musaro et al, 1999;Sakuma et al, 2003).…”

Section: Role Of Ca 2] -Dependent Transcriptional Pathways In Skmentioning

confidence: 99%

Ca²⁺/calmodulin‐dependent transcriptional pathways: potential mediators of skeletal muscle growth and development

Al-Shanti

Stewart

2009

Biological Reviews

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The loss of muscle mass with age and disuse has a significant impact on the physiological and social well-being of the aged; this is an increasingly important problem as the population becomes skewed towards older age. Exercise has psychological benefits but it also impacts on muscle protein synthesis and degradation, increasing muscle tissue volume in both young and older individuals. Skeletal muscle hypertrophy involves an increase in muscle mass and cross-sectional area and associated increased myofibrillar protein content. Attempts to understand the molecular mechanisms that underlie muscle growth, development and maintenance, have focused on characterising the molecular pathways that initiate, maintain and regenerate skeletal muscle. Such understanding may aid in improving targeted interventional therapies for age-related muscle loss and muscle wasting associated with diseases. Two major routes through which skeletal muscle development and growth are regulated are insulin-like growth factor I (IGF-I) and Ca(2+)/calmodulin-dependent transcriptional pathways. Many reviews have focused on understanding the signalling pathways of IGF-I and its receptor, which govern skeletal muscle hypertrophy. However, alternative molecular signalling pathways such as the Ca(2+)/calmodulin-dependent transcriptional pathways should also be considered as potential mediators of muscle growth. These latter pathways have received relatively little attention and the purpose herein is to highlight the progress being made in the understanding of these pathways and associated molecules: calmodulin, calmodulin kinases (CaMKs), calcineurin and nuclear factor of activated T-cell (NFAT), which are involved in skeletal muscle regulation. We describe: (1) how conformational changes in the Ca(2+) sensor calmodulin result in the exposure of binding pockets for the target proteins (CaMKs and calcineurin). (2) How Calmodulin consequently activates either the Ca(2+)/calmodulin-dependent kinases pathways (via CaMKs) or calmodulin-dependent serine/threonine phosphatases (via calcineurin). (3) How calmodulin kinases alter transcription in the nucleus through the phosphorylation, deactivation and translocation of histone deacetylase 4 (HDAC4) from the nucleus to the cytoplasm. (4) How calcineurin transmits signals to the nucleus through the dephosphorylation and translocation of NFAT from the cytoplasm to the nucleus.

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A Calcineurin-NFATc3-Dependent Pathway Regulates Skeletal Muscle Differentiation and Slow Myosin Heavy-Chain Expression

Cited by 67 publications

References 32 publications

Modulation of skeletal muscle fiber type by mitogen‐activated protein kinase signaling

Modulation of skeletal muscle fiber type by mitogen‐activated protein kinase signaling

NFATc1 activates the acetylcholinesterase promoter in rat muscle

Ca²⁺/calmodulin‐dependent transcriptional pathways: potential mediators of skeletal muscle growth and development

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A Calcineurin-NFATc3-Dependent Pathway Regulates Skeletal Muscle Differentiation and Slow Myosin Heavy-Chain Expression

Cited by 67 publications

References 32 publications

Modulation of skeletal muscle fiber type by mitogen‐activated protein kinase signaling

Modulation of skeletal muscle fiber type by mitogen‐activated protein kinase signaling

NFATc1 activates the acetylcholinesterase promoter in rat muscle

Ca2+/calmodulin‐dependent transcriptional pathways: potential mediators of skeletal muscle growth and development

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Ca²⁺/calmodulin‐dependent transcriptional pathways: potential mediators of skeletal muscle growth and development