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

ABSTRACT: 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.

SUBMITTER: Potthoff MJ

PROVIDER: S-EPMC1957540 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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

Potthoff Matthew J MJ Wu Hai H Arnold Michael A MA Shelton John M JM Backs Johannes J McAnally John J Richardson James A JA Bassel-Duby Rhonda R Olson Eric N EN

The Journal of clinical investigation 20070901 9

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 incre ...[more]

PMID: 17786239

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Project description:The contractile properties of fast-twitch and slow-twitch skeletal muscles are primarily determined by the myosin isoform content and modulated by a variety of sarcomere proteins. X-ray diffraction studies of regulatory mechanisms in muscle contraction have focused predominately on fast- or mixed-fibre muscle with slow muscle being much less studied. Here, we used time-resolved X-ray diffraction to investigate the dynamic behaviour of the myofilament proteins in relatively pure slow-twitch-fibre rat soleus (SOL) and pure fast-twitch-fibre rat extensor digitorum longus (EDL) muscle during twitch and tetanic contractions at optimal length. During twitch contractions the diffraction signatures indicating a transition in the myosin heads from ordered OFF states, where heads are held close to the thick filament backbone, to disordered ON states, where heads are free to bind to thin filaments, were found in EDL and not in SOL muscle. During tetanic contraction, changes in the disposition of myosin heads as active tension develops is a quasi-stepwise process in EDL muscle whereas in SOL muscle this relationship appears to be linear. The observed reduced extensibility of the thick filaments in SOL muscle as compared to EDL muscles indicates a molecular basis for this behaviour. These data indicate that for the EDL, thick filament activation is a cooperative strain-induced mechano-sensing mechanism, whereas for the SOL, thick filament activation has a more graded response. These different approaches to thick filament regulation in fast- and slow-twitch muscles may be adaptations for short-duration, strong contractions versus sustained, finely controlled contractions, respectively. KEY POINTS: Fast-twitch muscle and slow-twitch muscle are optimized for strong, short-duration contractions and for tonic postural activity, respectively. Structural events (OFF to ON transitions) in the myosin-containing thick filaments in fast muscle help determine the timing and strength of contractions, but these have not been studied in slow-twitch muscle. The X-ray diffraction signatures of structural OFF to ON transitions are different in fast extensor digitorum longus (EDL) and slow soleus (SOL) muscle, being completely absent during twitches in soleus muscle and blunted during tetanic contractions SOL as compared to EDL Quasi-stepwise thick filament structural OFF to ON transitions in fast twitch muscle may be an adaptation for rapid, ballistic movements, whereas more graded OFF to ON structural transitions in slow-twitch muscle may be an adaptation for slower, finer motions.

Project description:It has been shown that not only calcium but also strong binding myosin heads contribute to thin filament activation in isometrically contracting animal fast-twitch and cardiac muscle preparations. This behavior has not been studied in human muscle fibers or animal slow-twitch fibers. Human slow-twitch fibers are interesting since they contain the same myosin heavy chain isoform as the human heart. To explore myosin-induced activation of the thin filament in isometrically contracting human slow-twitch fibers, the endogenous troponin complex was exchanged for a well-characterized fast-twitch skeletal troponin complex labeled with the fluorescent dye N-((2-(Iodoacetoxy)ethyl)-N-methyl)amino-7-nitrobenz-2-oxa-1,3-diazole (fsTn-IANBD). The exchange was ?70% complete (n = 8). The relative contributions of calcium and strong binding cross-bridges to thin filament activation were dissected by increasing the concentration of calcium from relaxing (pCa 7.5) to saturating levels (pCa 4.5) before and after incubating the exchanged fibers in the myosin inhibitor para-aminoblebbistatin (AmBleb). At pCa 4.5, the relative contributions of calcium and strong binding cross-bridges to thin filament activation were ?69 and ?31%, respectively. Additionally, switching from isometric to isotonic contraction at pCa 4.5 revealed that strong binding cross-bridges contributed ?29% to thin filament activation (i.e., virtually the same magnitude obtained with AmBleb). Thus, we showed through two different approaches that lowering the number of strong binding cross-bridges, at saturating calcium, significantly reduced the activation of the thin filament in human slow-twitch fibers. The contribution of myosin to activation resembled that which was previously reported in rat cardiac and rabbit fast-twitch muscle preparations. This method could be applied to slow-twitch human fibers obtained from the soleus muscle of cardiomyopathy patients. Such studies could lead to a better understanding of the effect of point mutations of the cardiac myosin head on the regulation of muscle contraction and could lead to better management by pharmacological approaches.

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

Publications

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

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