Delineation of a slow-twitch-myofiber-specific transcriptional element by using in vivo somatic gene transfer.

Corin, Shari J.; Levitt, Linda K.; O'Mahoney, John V.; Joya, Josephine E.; Hardeman, Edna C.; Wade, Robert

doi:10.1073/pnas.92.13.6185

Cited by 49 publications

(45 citation statements)

References 22 publications

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“…In its promoterautonomy, the TnIfast IRE may differ from the TnIslow upstream enhancer. The latter does not appear to be capable of driving expression from the tk promoter in transgenic mice (Nakayama et al, 1996), although this enhancer/promoter combination has detectable function when assayed by direct gene transfer into adult muscle (Corin et al, 1995).…”

Section: Regulatory Capabilities Of the Irementioning

confidence: 96%

“…Cell culture transfection studies have identified important enhancers capable of activating heterologous reporter gene expression during myoblast differentiation, upstream of the TnIslow gene (termed USE or SURE) (Corin et al, 1994;Nakayama et al, 1996) and within the first intron of the TnIfast gene (termed IRE or FIRE) (Yutzey et al, 1989) and of the TnIslow gene (Zhu et al, 1995). Transgenic mouse studies, including direct analysis at the cellular level, have established that the TnIslow upstream enhancer drives slow fiber-type-specific expression (Corin et al, 1995;Nakayama et al, 1996); however, the fiber-type regulatory capabilities of the TnIfast IRE enhancer have not been characterized at the cellular level. In elegant transgenic mouse experiments, Nakayama et al (1996) and Calvo et al (2001) coupled the TnIfast enhancer, or a chimeric TnIfast/TnIslow enhancer containing the downstream half of the TnIfast IRE, to a minimal TnIslow promoter and found preferential expression in glycolytic, fast-fiber-enriched muscles compared with the soleus, an oxidative mixed fast/slow muscle.…”

Section: Introductionmentioning

confidence: 99%

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TnIfast IRE enhancer: Multistep developmental regulation during skeletal muscle fiber type differentiation

Hallauer

Hastings

2002

Developmental Dynamics

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To identify developmental steps leading to adult skeletal muscle fiber-type-specific gene expression, we carried out transgenic mouse studies of the IRE enhancer of the quail TnIfast gene. Histochemical analysis of IRE/herpesvirus tk promoter/␤-galactosidase reporter transgene expression in adult muscle directly demonstrated IRE-driven fast vs. slow fiber-type specificity, and IIB>IIX>IIA differential expression among the fast fiber types: patterns similar to those of native-promoter TnIfast constructs. These tissue-and cell-type specificities are autonomous to the IRE and do not depend on interactions with a muscle gene promoter. Developmental studies showed that the adult pattern of IRE-driven transgene expression emerges in three steps: (1) activation during the formation of primary embryonic (presumptive slow) muscle fibers; (2) activation, to markedly higher levels, during formation of secondary (presumptive fast) fibers, and (3) differential augmentation of expression during early postnatal maturation of the IIB, IIX, IIA fast fiber types. These results provide insight into the roles of gene activation and gene repression mechanisms in fiber-type specificity and can account for apparently disparate results obtained in previous studies of TnI isoform expression in development. Each of the three IRE-driven developmental steps is spatiotemporally associated with a different major regulatory event at the fast myosin heavy chain gene cluster, suggesting that diverse muscle gene families respond to common, or tightly integrated, regulatory signals during multiple steps of muscle fiber differentiation.

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Section: Regulatory Capabilities Of the Irementioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

TnIfast IRE enhancer: Multistep developmental regulation during skeletal muscle fiber type differentiation

Hallauer

Hastings

2002

Developmental Dynamics

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“…Work on other slow isoform contractile protein genes, such as the TnIslow and TnCslow genes, has demonstrated that MEF2, E-box, and CACC box sites are important in directing slow skeletal muscle specific expression (15,16,33,34). To address potential functional roles of these three sites within the 270-bp MLC2slow promoter, we individually mutated the E-box, MEF2, and CACC sites (Fig.…”

Section: Deletion and Mutational Analyses Of The Mlc2slow Promoter-prmentioning

confidence: 99%

The CACC Box and Myocyte Enhancer Factor-2 Sites within the Myosin Light Chain 2 Slow Promoter Cooperate in Regulating Nerve-specific Transcription in Skeletal Muscle

Esser

Nelson

Lupa-Kimball

et al. 1999

Journal of Biological Chemistry

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Previous experiments showed that activity of the ؊800-base pair MLC2slow promoter was 75-fold higher in the innervated soleus (SOL) compared with the noninnervated SOL muscles. Using in vivo DNA injection of MLC2slow promoter-luciferase constructs, the aim of this project was to identify regulatory sites and potential transcription factors important for slow nerve-dependent gene expression. Three sites within the proximal promoter (myocyte enhancer factor-2 (MEF2), E-box, and CACC box) were individually mutated, and the effect on luciferase expression was determined. There was no change in luciferase expression in the SOL and extensor digitorum longus (EDL) muscles when the E-box was mutated. In contrast, the MEF2 mutation resulted in a 30-fold decrease in expression in the innervated SOL muscles (10.3 versus 0.36 normalized relative light units (RLUs)). Transactivation of the MLC2slow promoter by overexpressing MEF2 was only seen in the innervated SOL (676,340 versus 2,225,957 RLUs; p < 0.01) with no effect in noninnervated SOL or EDL muscles. These findings suggest that the active MLC2slow promoter is sensitive to MEF2 levels, but MEF2 levels alone do not determine nerve-dependent expression. Mutation of the CACC box resulted in a significant up-regulation in the EDL muscles (0.23 versus 4.08 normalized RLUs). With the CACC box mutated, overexpression of MEF2 was sufficient to transactivate the MLC2slow promoter in noninnervated SOL muscles (27,536 versus 1,605,797 RLUs). Results from electrophoretic mobility shift and supershift assays confirm MEF2 protein binding to the MEF2 site and demonstrate specific binding to the CACC sequence. These results suggest a model for nerve-dependent regulation of the MLC2slow promoter in which derepression occurs through the CACC box followed by quantitative expression through enhanced MEF2 activation.

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“…Activated calcineurin exposes the nuclear localization signal of NFAT, resulting in its nuclear translocation (11). Conversely, GSK-3␤-dependent phosphorylation masks the nuclear localization signal, resulting in nuclear export of NFAT and termination of calcineurin-induced gene transcription (12, 13).Although NFAT was identified in T-cells, several studies have postulated a role for NFAT in skeletal muscle gene expression (14,15). Five NFAT isoforms have been identified (16), and four isoforms (NFATc1, -c2, -c3, and -5) are expressed in skeletal muscle (17, 18).…”

mentioning

confidence: 99%

“…Although NFAT was identified in T-cells, several studies have postulated a role for NFAT in skeletal muscle gene expression (14,15). Five NFAT isoforms have been identified (16), and four isoforms (NFATc1, -c2, -c3, and -5) are expressed in skeletal muscle (17, 18).…”

mentioning

confidence: 99%

Glycogen Synthase Kinase 3β Suppresses Myogenic Differentiation through Negative Regulation of NFATc3

Velden

Schols

Willems

et al. 2008

Journal of Biological Chemistry

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Skeletal muscle atrophy is a prominent and disabling feature in many chronic diseases. Prevention or reversal of muscle atrophy by stimulation of skeletal muscle growth could be an important therapeutic strategy. Glycogen synthase kinase 3␤ (GSK-3␤) has been implicated in the negative regulation of skeletal muscle growth. Since myogenic differentiation is an essential part of muscle growth, we investigated if inhibition of GSK-3␤ is sufficient to stimulate myogenic differentiation and whether this depended on regulation of the transcription factor nuclear factor of activated T-cells (NFAT). In both myogenically converted mouse embryonic fibroblasts and C2C12 myoblasts, deficiency of GSK-3␤ protein (activity) resulted in enhanced myotube formation and muscle-specific gene expression during differentiation, which was reversed by reintroduction of wild type but not kinase-inactive (K85R) GSK-3␤. In addition, GSK-3␤ inhibition restored myogenic differentiation following calcineurin blockade, which suggested the involvement of NFAT. GSK-3␤-deficient mouse embryonic fibroblasts or myoblasts displayed enhanced nuclear translocation of NFATc3 and elevated NFAT-sensitive promoter transactivation, which was reduced by reintroducing wild type, but not K85R GSK-3␤. Overexpression of NFATc3 increased muscle gene promoter transactivation, which was abolished by co-expression of wild type GSK-3␤. Finally, stimulation of muscle gene expression observed following GSK-3␤ inhibition was strongly attenuated in NFATc3-deficient myoblasts, indicating that this response requires NFATc3. Collectively, our data demonstrate negative regulation of myogenic differentiation by GSK-3␤ through a transcriptional mechanism that depends on NFATc3. Inhibition of GSK-3␤ may be a potential strategy in prevention or treatment of muscle atrophy.Maintenance of muscle mass is critical for health, and loss of skeletal muscle mass compromises human physical condition and survival in chronic diseases, such as chronic obstructive pulmonary disease (1, 2). Restoring lost muscle mass is important for improving quality of life and ultimately disease prognosis (3). To restore muscle mass and improve muscle function in various diseases conditions, a better understanding of the molecular mechanisms of skeletal muscle (re)growth is required. Skeletal muscle differentiation is a critical element of certain types of postnatal growth of the skeletal musculature and is mainly dependent on satellite cells (quiescent myoblasts), which upon activation proliferate, differentiate, and fuse with existing muscle fibers or with each other to form new myofibers (4). Myoblast fusion allows additional muscle growth by myonuclear accretion, beyond the limitations imposed by the myonuclear domain (i.e. the maximal cytoplasm/nucleus ratio) (5).The protein kinase GSK-3 2 is ubiquitously expressed, and, although it was originally identified as a suppressor of glycogen synthase (6), GSK-3 has been implicated in a myriad of metabolic and signaling pathways (7). Recent studies have ide...

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Delineation of a slow-twitch-myofiber-specific transcriptional element by using in vivo somatic gene transfer.

Abstract: ABSTRACT

Cited by 49 publications

References 22 publications

TnIfast IRE enhancer: Multistep developmental regulation during skeletal muscle fiber type differentiation

TnIfast IRE enhancer: Multistep developmental regulation during skeletal muscle fiber type differentiation

The CACC Box and Myocyte Enhancer Factor-2 Sites within the Myosin Light Chain 2 Slow Promoter Cooperate in Regulating Nerve-specific Transcription in Skeletal Muscle

Glycogen Synthase Kinase 3β Suppresses Myogenic Differentiation through Negative Regulation of NFATc3

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