Concerted regulation of myofiber-specific gene expression and muscle performance by the transcriptional repressor Sox6

Quiat, Daniel; Voelker, Kevin A.; Pei, Jimin; Grishin, Nick V.; Grange, Robert W.; Bassel‐Duby, Rhonda; Olson, Eric N.

doi:10.1073/pnas.1107413108

Cited by 129 publications

(129 citation statements)

References 31 publications

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“…Consistent with this, overexpression of Sox6 has been shown to repress transcription of the slow-twitch-specific -MHC and troponin genes and to cause a concomitant increase in slow-twitch and decrease in fast-twitch muscle fibres in transgenic mice (van Rooij et al, 2009), and very recent studies have demonstrated that Sox6 binds to conserved cisregulatory elements in slow-twitch fibre genes to represses their transcription in adult fast-twitch muscle (Quiat et al, 2011). Little is known about how the lineage-specific activity of Sox6 is regulated in mammals; however, a role for the microRNA miR-499 has been suggested, based upon the finding that the 3ЈUTRs of human, mouse and rat Sox6 contain between 1 and 4 consensus recognition sites for the miR-499 SEED sequence and the demonstration that miR-499 reduces Sox6 mRNA levels both in vitro and in vivo (McCarthy et al, 2009;van Rooij et al, 2009;Bell et al, 2010).…”

Section: Introductionmentioning

confidence: 60%

Prdm1a and miR-499 act sequentially to restrict Sox6 activity to the fast-twitch muscle lineage in the zebrafish embryo

et al. 2011

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SUMMARYSox6 has been proposed to play a conserved role in vertebrate skeletal muscle fibre type specification. In zebrafish, sox6 transcription is repressed in slow-twitch progenitors by the Prdm1a transcription factor. Here we identify sox6 cis-regulatory sequences that drive fast-twitch-specific expression in a Prdm1a-dependent manner. We show that sox6 transcription subsequently becomes derepressed in slow-twitch fibres, whereas Sox6 protein remains restricted to fast-twitch fibres. We find that translational repression of sox6 is mediated by miR-499, the slow-twitch-specific expression of which is in turn controlled by Prdm1a, forming a regulatory loop that initiates and maintains the slow-twitch muscle lineage.

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Section: Introductionmentioning

confidence: 60%

Prdm1a and miR-499 act sequentially to restrict Sox6 activity to the fast-twitch muscle lineage in the zebrafish embryo

et al. 2011

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“…Two miRNAs implicated previously in muscle fibertype programs (19) were differentially regulated: miR-208b, which is encoded within the Myh7 gene, and miR-499, which is encoded within the Myh7b gene. miR-499 and miR-208b, which target the same mRNA targets, have been shown to drive a slow-twitch program by downregulating transcriptional repressors of slow-twitch contractile protein genes, such as Sox6 (19,20). Expression of miR- 208b was significantly increased in MCK-PPARβ/δ muscle but was undetectable in MCK-PPARα muscle (Figure 2A and Supplemental Figure 3).…”

Section: Mck-ppar Transgenic Lines Exhibit Strikingly Different Musclmentioning

confidence: 93%

“…However, highly conserved sequences that conformed to the consensus binding sites for ERR were identified in both promoter regions ( Figure 4A). The putative Myh7 ERR binding site is located well upstream of the well-described proximal promoter elements known to respond to the thyroid receptor, MCAT, and Sox6 (20,21). Notably, ERRγ has been shown recently to activate oxidative muscle fiber programs in a manner similar to that of PPARβ/δ (14,22).…”

Section: The Nuclear Receptor Errγ Functions Downstream Of Pparβ/δ Tomentioning

confidence: 99%

Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism

Gan¹,

Rumsey²,

Hazen³

et al. 2013

J. Clin. Invest.

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The mechanisms involved in the coordinate regulation of the metabolic and structural programs controlling muscle fitness and endurance are unknown. Recently, the nuclear receptor PPARβ/δ was shown to activate muscle endurance programs in transgenic mice. In contrast, muscle-specific transgenic overexpression of the related nuclear receptor, PPARα, results in reduced capacity for endurance exercise. We took advantage of the divergent actions of PPARβ/δ and PPARα to explore the downstream regulatory circuitry that orchestrates the programs linking muscle fiber type with energy metabolism. Our results indicate that, in addition to the well-established role in transcriptional control of muscle metabolic genes, PPARβ/δ and PPARα participate in programs that exert opposing actions upon the type I fiber program through a distinct muscle microRNA (miRNA) network, dependent on the actions of another nuclear receptor, estrogen-related receptor γ (ERRγ). Gain-of-function and loss-of-function strategies in mice, together with assessment of muscle biopsies from humans, demonstrated that type I muscle fiber proportion is increased via the stimulatory actions of ERRγ on the expression of miR-499 and miR-208b. This nuclear receptor/miRNA regulatory circuit shows promise for the identification of therapeutic targets aimed at maintaining muscle fitness in a variety of chronic disease states, such as obesity, skeletal myopathies, and heart failure.

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“…H&E staining, NADH staining, metachromatic ATPase staining, Evans blue dye uptake experiments, succinic dehydrogenase staining, and immunohistochemistry were performed as previously described (50)(51)(52)(53). More information is provided in SI Methods.…”

Section: Methodsmentioning

confidence: 99%

Histone deacetylases 1 and 2 regulate autophagy flux and skeletal muscle homeostasis in mice

Moresi

Carrer

Grueter

et al. 2012

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

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117

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Maintenance of skeletal muscle structure and function requires efficient and precise metabolic control. Autophagy plays a key role in metabolic homeostasis of diverse tissues by recycling cellular constituents, particularly under conditions of caloric restriction, thereby normalizing cellular metabolism. Here we show that histone deacetylases (HDACs) 1 and 2 control skeletal muscle homeostasis and autophagy flux in mice. Skeletal muscle-specific deletion of both HDAC1 and HDAC2 results in perinatal lethality of a subset of mice, accompanied by mitochondrial abnormalities and sarcomere degeneration. Mutant mice that survive the first day of life develop a progressive myopathy characterized by muscle degeneration and regeneration, and abnormal metabolism resulting from a blockade to autophagy. HDAC1 and HDAC2 regulate skeletal muscle autophagy by mediating the induction of autophagic gene expression and the formation of autophagosomes, such that myofibers of mice lacking these HDACs accumulate toxic autophagic intermediates. Strikingly, feeding HDAC1/2 mutant mice a high-fat diet from the weaning age releases the block in autophagy and prevents myopathy in adult mice. These findings reveal an unprecedented and essential role for HDAC1 and HDAC2 in maintenance of skeletal muscle structure and function and show that, at least in some pathological conditions, myopathy may be mitigated by dietary modifications.autophagosome formation | muscle disease | muscle metabolism | epigenetic regulation C ellular homeostasis is maintained by a balance between protein biosynthesis and degradation. Macroautophagy (herein referred to as autophagy) is a catabolic pathway responsible for the degradation of various cellular constituents or deleterious cellular components. The process involves formation of vesicles, called autophagosomes, that capture and deliver proteins to lysosomes for degradation (1). The resulting breakdown products are recycled and used to support cellular metabolism (2). Genetic studies with mice mutant for genes involved in autophagy substantiated the importance of basal autophagy for organelle turnover and cellular homeostasis (3-11). Various stress conditions, such as fasting, exercise, hypoxia, oxidative stress, and pathogen infection, trigger autophagy as an adaptive response to normalize cellular metabolism (12, 13).Deregulation of autophagy has been implicated in cancer (14, 15), neurodegenerative disorders (4, 5, 10), and muscular diseases (16,17). Epigenetic factors have been implicated in regulating autophagy during various pathological conditions (12). Alteration of the acetylation status of histones or other proteins through histone deacetylases (HDACs) is a key mechanism that controls gene transcription and protein function. Removal of acetyl groups from histone tails by HDACs promotes transcriptional repression by allowing chromatin compaction (18). HDACs also modulate the activity of a variety of transcription factors and large macromolecular complexes involved in diverse cellular processes (19)....

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Concerted regulation of myofiber-specific gene expression and muscle performance by the transcriptional repressor Sox6

Cited by 129 publications

References 31 publications

Prdm1a and miR-499 act sequentially to restrict Sox6 activity to the fast-twitch muscle lineage in the zebrafish embryo

Prdm1a and miR-499 act sequentially to restrict Sox6 activity to the fast-twitch muscle lineage in the zebrafish embryo

Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism

Histone deacetylases 1 and 2 regulate autophagy flux and skeletal muscle homeostasis in mice

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