title: 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.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Potthoff
authors.forename: Hai
authors.initials: H
authors.lastname: Wu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Arnold
authors.forename: John M
authors.initials: JM
authors.lastname: Shelton
authors.forename: Johannes
authors.initials: J
authors.lastname: Backs
authors.forename: John
authors.initials: J
authors.lastname: McAnally
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006655:Histone Deacetylases / Q000145:classification / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000145:classification / Q000235:genetics / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D064326:MEF2 Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D010084:Oxidation-Reduction; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D025801:Ubiquitin / Q000378:metabolism