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J. Biol. Chem., Vol. 281, Issue 29, 20085-20094, July 21, 2006

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Cardiotonic Steroids Stimulate Glycogen Synthesis in Human Skeletal Muscle Cells via a Src- and ERK1/2-dependent Mechanism^*

Olga Kotova, Lubna Al-Khalili, Sara Talia, Catherine Hooke, Olga V. Fedorova, Alexei Y. Bagrov, and Alexander V. Chibalin¹

From the Section of Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 77 Stockholm, Sweden and the Laboratory of Cardiovascular Science, NIA, National Institutes of Health, Baltimore, Maryland 21224

The cardiotonic steroid, ouabain, a specific inhibitor of Na⁺,K⁺-ATPase, initiates protein-protein interactions that lead to an increase in growth and proliferation in different cell types. We explored the effects of ouabain on glucose metabolism in human skeletal muscle cells (HSMC) and clarified the mechanisms of ouabain signal transduction. In HSMC, ouabain increased glycogen synthesis in a concentration-dependent manner reaching the maximum at 100 nM. The effect of ouabain was additive to the effect of insulin and was independent of phosphatidylinositol 3-kinase inhibitor LY294002 but was abolished in the presence of a MEK1/2 inhibitor (PD98059) or a Src inhibitor (PP2). Ouabain increased Src-dependent tyrosine phosphorylation of ₁- and ₂-subunits of Na⁺,K⁺-ATPase and promoted interaction of ₁- and ₂-subunits with Src, as assessed by co-immunoprecipitation with Src. Phosphorylation of ERK1/2 and GSK3/, as well as p90rsk activity, was increased in response to ouabain in HSMC, and these responses were prevented in the presence of PD98059 and PP2. Incubation of HSMC with 100 nM ouabain increased phosphorylation of the-subunits of the Na-pump at a MAPK-specific Thr-Pro motif. Ouabain treatment decreased the surface abundance of ₂-subunit, whereas abundance of the ₁-subunit was unchanged. Marinobufagenin, an endogenous vertebrate bufadienolide cardiotonic steroid, increased glycogen synthesis in HSMC at 10 nM concentration, similarly to 100 nM ouabain. In conclusion, ouabain and marinobufagenin stimulate glycogen synthesis in skeletal muscle. This effect is mediated by activation of a Src-, ERK1/2-, p90rsk-, and GSK3-dependent signaling pathway.

Received for publication, February 17, 2005 , and in revised form, April 18, 2006.

^* This work was supported by grants from the Swedish Research Council, the Swedish Heart and Lung Foundation, the Novo-Nordisk Foundation, the Swedish Society of Medicine, and the NIA, National Institutes of Health Intramural Research Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Molecular Medicine and Surgery, Section of Integrative Physiology, Karolinska Institutet, von Eulers väg 4, 4 tr, SE-171 77, Stockholm, Sweden. Tel.: 46-8-524-87-584; Fax: 46-8-335436; E-mail: Alexander.Chibalin{at}ki.se.

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