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This Article Full Text Full Text (PDF) All Versions of this Article: 294/4/E668    most recent 00640.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Nedachi, T. Articles by Kanzaki, M. PubMed PubMed Citation Articles by Nedachi, T. Articles by Kanzaki, M.

Ambient glucose levels qualify the potency of insulin myogenic actions by regulating SIRT1 and FoxO3a in C₂C₁₂ myocytes

¹Division of Biomaterials, Tohoku University Biomedical Engineering Research Organization; ²21st COE program "CRESCENDO", Graduate School of Pharmaceutical Sciences; ³Division of Advanced Therapeutics for Metabolic Diseases, Center for Translational and Advanced Animal Research; and ⁴Center for Research Strategy and Support, Tohoku University, Sendai, Japan

Submitted 3 October 2007 ; accepted in final form 18 January 2008

Nutrition availability is one of the major environmental signals influencing cell fate, such as proliferation, differentiation, and apoptosis, often functioning in concert with other humoral factors, including insulin. Herein, we show that low-serum-induced differentiation of C₂C₁₂ myocytes is significantly hampered under low glucose (LG; 5 mM) compared with high glucose (HG; 22.5 mM) conditions, concurrently with nuclear accumulation of SIRT1, an NAD⁺-dependent deacetylase, and FoxO3a, both of which are implicated in the negative regulation of myogenesis. Intriguingly, insulin appears to exert opposite actions, depending on glucose availability, with regard to the regulation of SIRT1 and FoxO3a abundance, which apparently contributes to modulating the potency of insulin's myogenic action. Namely, insulin exerts a potent myogenic effect in the presence of sufficient glucose, whereas insulin is unable to exert its myogenic action under LG conditions, since insulin evokes massive upregulation of both SIRT1 and FoxO3a in the absence of sufficient ambient glucose. In addition, the hampered differentiation state under LG is significantly restored by sirtinol, a SIRT1 inhibitor, whereas insulin abolished this sirtinol-dependent restoration, indicating that insulin can function as a negative as well as a positive myogenic factor depending on glucose availability. Taken together, our data reveal the importance of ambient glucose levels in the regulation of myogenesis and also in the determination of insulin's myogenic potency, which is achieved, at least in part, through regulation of the cellular contents and localization of SIRT1 and FoxO3a in differentiating C₂C₁₂ myocytes.

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