title: Concerted regulation of myofiber-specific gene expression and muscle performance by the transcriptional repressor Sox6.
abstract: In response to physiological stimuli, skeletal muscle alters its myofiber composition to significantly affect muscle performance and metabolism. This process requires concerted regulation of myofiber-specific isoforms of sarcomeric and calcium regulatory proteins that couple action potentials to the generation of contractile force. Here, we identify Sox6 as a fast myofiber-enriched repressor of slow muscle gene expression in vivo. Mice lacking Sox6 specifically in skeletal muscle have an increased number of slow myofibers, elevated mitochondrial activity, and exhibit down-regulation of the fast myofiber gene program, resulting in enhanced muscular endurance. In addition, microarray profiling of Sox6 knockout muscle revealed extensive muscle fiber-type remodeling, and identified numerous genes that display distinctive fiber-type enrichment. Sox6 directly represses the transcription of slow myofiber-enriched genes by binding to conserved cis-regulatory elements. These results identify Sox6 as a robust regulator of muscle contractile phenotype and metabolism, and elucidate a mechanism by which functionally related muscle fiber-type specific gene isoforms are collectively controlled.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Quiat
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Voelker
authors.forename: Jimin
authors.initials: J
authors.lastname: Pei
authors.forename: Nick V
authors.initials: NV
authors.lastname: Grishin
authors.forename: Robert W
authors.initials: RW
authors.lastname: Grange
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D009119:Muscle Contraction / Q000502:physiology; D018656:Muscle Fibers, Fast-Twitch / Q000166:cytology / Q000502:physiology*; D018657:Muscle Fibers, Slow-Twitch / Q000166:cytology / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology*; D055755:SOXD Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D055755:SOXD Transcription Factors; C095939:Sox6 protein, mouse; D002118:Calcium