Histone deacetylase degradation and MEF2 activation promote the formation of slow-twitch myofibers

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 10/2007; 117(9):2459-67. DOI: 10.1172/JCI31960
Source: PubMed


Skeletal muscle is composed of heterogeneous myofibers with distinctive rates of contraction, metabolic properties, and susceptibility to fatigue. We show that class II histone deacetylase (HDAC) proteins, which function as transcriptional repressors of the myocyte enhancer factor 2 (MEF2) transcription factor, fail to accumulate in the soleus, a slow muscle, compared with fast muscles (e.g., white vastus lateralis). Accordingly, pharmacological blockade of proteasome function specifically increases expression of class II HDAC proteins in the soleus in vivo. Using gain- and loss-of-function approaches in mice, we discovered that class II HDAC proteins suppress the formation of slow twitch, oxidative myofibers through the repression of MEF2 activity. Conversely, expression of a hyperactive form of MEF2 in skeletal muscle of transgenic mice promotes the formation of slow fibers and enhances running endurance, enabling mice to run almost twice the distance of WT littermates. Thus, the selective degradation of class II HDACs in slow skeletal muscle provides a mechanism for enhancing physical performance and resistance to fatigue by augmenting the transcriptional activity of MEF2. These findings provide what we believe are new insights into the molecular basis of skeletal muscle function and have important implications for possible therapeutic interventions into muscular diseases.

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Available from: Matthew J Potthoff, Aug 08, 2014
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    • "Further studies would be required to determine the role of HDAC4 in adult muscle remodeling. It is important to point out that inactivation of HDAC4 alone is not capable of " switching " fiber-types in vivo (Potthoff et al., 2007b), which reflects the functional redundancy of class IIa HDACs. Indeed, the closely-related HDAC5 can also suppress MEF2- dependent PGC-1α expression and is subjected to phosphorylation-dependent nuclear export (Czubryt et al., 2003; Vega et al., 2004). "
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    ABSTRACT: Fiber type-specific programs controlled by the transcription factor MEF2 dictate muscle functionality. Here, we show that HDAC4, a potent MEF2 inhibitor, is predominantly localized to the nuclei in fast/glycolytic fibers in contrast to the sarcoplasm in slow/oxidative fibers. The cytoplasmic localization is associated with HDAC4 hyper-phosphorylation in slow/oxidative-fibers. Genetic reprogramming of fast/glycolytic fibers to oxidative fibers by active CaMKII or calcineurin leads to increased HDAC4 phosphorylation, HDAC4 nuclear export, and an increase in markers associated with oxidative fibers. Indeed, HDAC4 represses the MEF2-dependent, PGC-1α-mediated oxidative metabolic gene program. Thus differential phosphorylation and localization of HDAC4 contributes to establishing fiber type-specific transcriptional programs.
    Molecules and Cells 02/2015; 38(4). DOI:10.14348/molcells.2015.2278 · 2.09 Impact Factor
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    • "The molecular basis of fiber type-specific gene expression is still not clear. A number of proteins have been suggested to control slow (MEF2 [Wu et al., 2000; Potthoff et al., 2007], myogenin [Hughes et al., 1993], PGC-1a [Lin et al., 2002]), and fast (MyoD [Hughes et al., 1993], the six transcription factors six4 and six1 and the cofactors Eya1 and Vp16 [Grifone et al., 2004, 2005; Niro et al., 2010; Richard et al., 2011]) muscle protein expression. Reciprocally, the slow muscle program can be transcriptionally repressed by the transcription factor sox6, which also regulates part of the fast myogenic program [Hagiwara et al., 2005, 2007; Quiat et al., 2011]. "
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    ABSTRACT: Skeletal muscle phenotype is regulated by a complex interaction between genetic, hormonal, and electrical inputs. However, because of the interrelatedness of these factors in vivo it is difficult to determine the importance of one over the other. Over the last 5 years, we have engineered skeletal muscles in the European Union (EU) and the United States (US) using the same clone of C2C12 cells. Strikingly, the dynamics of contraction of the muscles was dramatically different. Therefore, in this study we sought to determine whether the hormonal milieu (source of fetal bovine serum (FBS)) could alter engineered muscle phenotype. In muscles engineered in serum of US origin time-to-peak tension (2.2-fold), half relaxation (2.6-fold) and fatigue resistance (improved 25%) all showed indications of a shift towards a slower phenotype. Even though there was a dramatic shift in the rate of contraction, myosin heavy chain expression was the same. The contraction speed was instead related to a shift in calcium release/sensitivity proteins (DHPR=3.1-fold lower, slow CSQ=3.4-fold higher, and slow TnT=2.4-fold higher) and calcium uptake proteins (slow SERCA=1.7-fold higher and parvalbumin=41-fold lower). These shifts in calcium dynamics were accompanied by a partial shift in metabolic enzymes, but could not be explained by purported regulators of muscle phenotype. These data suggest that hormonal differences in serum of USDA and EU origin cause a shift in calcium handling resulting in a dramatic change in engineered muscle function. J. Cell. Biochem. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Biochemistry 12/2014; 115(12). DOI:10.1002/jcb.24938 · 3.26 Impact Factor
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    • "Genetic deletion of multiple class IIa HDACs in skeletal muscle promoted derepression of MEF2 target genes and the corresponding metabolic reprogramming of glycolytic to oxidative fibers (Potthoff et al., 2007). Furthermore, it has been suggested that direct HDAC3-dependent deacetylation of MEF2 may be another mode of MEF2 regulation in myogenesis (Gré goire et al., 2007). "
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    ABSTRACT: Metabolic homeostasis requires that cellular energy levels are adapted to environmental cues. This adaptation is largely regulated at the transcriptional level, through the interaction between transcription factors, coregulators, and the basal transcriptional machinery. Coregulators, which function as both metabolic sensors and transcriptional effectors, are ideally positioned to synchronize metabolic pathways to environmental stimuli. The balance between inhibitory actions of corepressors and stimulatory effects of coactivators enables the fine-tuning of metabolic processes. This tight regulation opens therapeutic opportunities to manage metabolic dysfunction by directing the activity of cofactors toward specific transcription factors, pathways, or cells/tissues, thereby restoring whole-body metabolic homeostasis.
    Cell metabolism 04/2014; 20(1). DOI:10.1016/j.cmet.2014.03.027 · 17.57 Impact Factor
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