title: FoxO6 and PGC-1α form a regulatory loop in myogenic cells.
abstract: Transcription factors of the FoxO (forkhead box O) family regulate a wide range of cellular physiological processes, including metabolic adaptation and myogenic differentiation. The transcriptional activity of most FoxO members is inhibitory to myogenic differentiation and overexpression of FoxO1 inhibits the development of oxidative type I fibres in vivo. In this study, we found that FoxO6, the last discovered FoxO family member, is expressed ubiquitously in various tissues but with higher expression levels in oxidative tissues, such as brain and oxidative muscles. Both the expression level and promoter activity of FoxO6 were found to be enhanced by PGC-1α (peroxisome-proliferator-activated receptor γ co-activator 1α), thus explained its enriched expression in oxidative tissues. We further demonstrated that FoxO6 represses the expression of PGC-1α via direct binding to an upstream A/T-rich element (AAGATATCAAAACA,-2228-2215) in the PGC-1α promoter. Oxidative low-intensity exercise induced PGC-1α but reduced FoxO6 expression levels in hind leg muscles, and the binding of FoxO6 to PGC-1α promoter was also prevented by exercise. As FoxO6 promoter can be co-activated by PGC-1α and its promoter in turn can be repressed by FoxO6, it suggests that FoxO6 and PGC-1α form a regulatory loop for setting oxidative metabolism level in the skeletal muscle, which can be entrained by exercise.
authors: Department of Life Sciences, National Central University, Jhongli 32001, Taiwan.
authors: Shih Ying
authors: SY
authors: Chung
authors: Wei Chieh
authors: WC
authors: Huang
authors: Ching Wen
authors: CW
authors: Su
authors: Kuan Wei
authors: KW
authors: Lee
authors: Hsiang Cheng
authors: HC
authors: Chi
authors: Cheng Tao
authors: CT
authors: Lin
authors: Szu-Tah
authors: ST
authors: Chen
authors: Kai Min
authors: KM
authors: Huang
authors: Mu Shiun
authors: MS
authors: Tsai
authors: Hui Peng
authors: HP
authors: Yu
authors: Shen Liang
authors: SL
authors: Chen
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D032446:Myoblasts / Q000378:metabolism*; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C525395:Foxo6 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors
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