title: Baf60c drives glycolytic metabolism in the muscle and improves systemic glucose homeostasis through Deptor-mediated Akt activation.
abstract: A shift from oxidative to glycolytic metabolism has been associated with skeletal muscle insulin resistance in type 2 diabetes. However, whether this metabolic switch is deleterious or adaptive remains under debate, in part because of a limited understanding of the regulatory network that directs the metabolic and contractile specification of fast-twitch glycolytic muscle. Here we show that Baf60c (also called Smarcd3), a transcriptional cofactor enriched in fast-twitch muscle, promotes a switch from oxidative to glycolytic myofiber type through DEP domain-containing mTOR-interacting protein (Deptor)-mediated Akt activation. Muscle-specific transgenic expression of Baf60c activates a program of molecular, metabolic and contractile changes characteristic of glycolytic muscle. In addition, Baf60c is required for maintaining glycolytic capacity in adult skeletal muscle in vivo. Baf60c expression is significantly lower in skeletal muscle from obese mice compared to that from lean mice. Activation of the glycolytic muscle program by transgenic expression of Baf60c protects mice from diet-induced insulin resistance and glucose intolerance. Further mechanistic studies revealed that Deptor is induced by the Baf60c-Six4 transcriptional complex and mediates activation of Akt and glycolytic metabolism by Baf60c in a cell-autonomous manner. This work defines a fundamental mechanism underlying the specification of fast-twitch glycolytic muscle and illustrates that the oxidative-to-glycolytic metabolic shift in skeletal muscle is potentially adaptive and beneficial in the diabetic state.
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Zhuo-Xian
authors.initials: ZX
authors.lastname: Meng
authors.forename: Siming
authors.initials: S
authors.lastname: Li
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Hwi Jin
authors.initials: HJ
authors.lastname: Ko
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Lee
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Jung
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Okutsu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.forename: Jiandie D
authors.initials: JD
authors.lastname: Lin
mesh_terms: D000818:Animals; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism / Q000502:physiology*; D016000:Cluster Analysis; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006706:Homeostasis; D006801:Humans; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000378:metabolism / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism; D009132:Muscles / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D019076:Transgenes
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C491649:SMARCD3 protein, human; C494055:Smarcd3 protein, mouse; D014157:Transcription Factors; C570841:deptor protein, mouse; C556139:DEPTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
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