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

Matthew J. Potthoff, Hai Wu, Michael A. Arnold, John M. Shelton, Johannes Backs, John McAnally, James A. Richardson, Rhonda Bassel-Duby, Eric N. Olson

Research output: Contribution to journalArticle

250 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2459-2467
Number of pages9
JournalJournal of Clinical Investigation
Volume117
Issue number9
DOIs
StatePublished - Sep 4 2007

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MEF2 Transcription Factors
Histone Deacetylases
Skeletal Muscle
Fatigue
Muscles
Proteins
Quadriceps Muscle
Muscular Diseases
Proteasome Endopeptidase Complex
Transgenic Mice
Transcription Factors
Pharmacology

ASJC Scopus subject areas

  • Medicine(all)

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Histone deacetylase degradation and MEF2 activation promote the formation of slow-twitch myofibers. / Potthoff, Matthew J.; Wu, Hai; Arnold, Michael A.; Shelton, John M.; Backs, Johannes; McAnally, John; Richardson, James A.; Bassel-Duby, Rhonda; Olson, Eric N.

In: Journal of Clinical Investigation, Vol. 117, No. 9, 04.09.2007, p. 2459-2467.

Research output: Contribution to journalArticle

Potthoff, Matthew J. ; Wu, Hai ; Arnold, Michael A. ; Shelton, John M. ; Backs, Johannes ; McAnally, John ; Richardson, James A. ; Bassel-Duby, Rhonda ; Olson, Eric N. / Histone deacetylase degradation and MEF2 activation promote the formation of slow-twitch myofibers. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 9. pp. 2459-2467.
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