Enhanced Mitogenic Signaling in Skeletal Muscle of Women With Polycystic Ovary Syndrome Anne Corbould 1 2 , Haiyan Zhao 1 , Salida Mirzoeva 1 , Fraser Aird 1 and Andrea Dunaif 1 2 1 Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 2 Division of Women’s Health, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts Address correspondence and reprint requests to Andrea Dunaif, MD, Division of Endocrinology, MetabolismMolecular Medicine, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Chicago, IL 60611. E-mail: a-dunaif{at}northwestern.edu Abstract Insulin resistance in polycystic ovary syndrome (PCOS) results from a postbinding defect in signaling. Insulin receptor and insulin receptor substrate (IRS)-1 serine hyperphosphorylation by an unidentified kinase(s) contributes to this defect. We investigated whether insulin resistance is selective, affecting metabolic but not mitogenic pathways, in skeletal muscle as it is in cultured skin fibroblasts in PCOS. Extracellular signal–regulated kinase (ERK)1/2 activation was increased in skeletal muscle tissue and in cultured myotubes basally and in response to insulin in women with PCOS compared with control women. Mitogen-activated/extracellular signal–regulated kinase kinase (MEK)1/2 was also activated in PCOS, whereas p38 mitogen-activated protein kinase phosphorylation and signaling from the insulin receptor to Grb2 was similar in both groups. The activity of p21Ras was decreased and Raf-1 abundance increased in PCOS, suggesting that altered mitogenic signaling began at this level. MEK1/2 inhibition reduced IRS-1 Ser 312 phosphorylation and increased IRS-1 association with the p85 subunit of phosphatidylinositol 3-kinase in both groups. We conclude that in PCOS skeletal muscle, 1 ) mitogenic signaling is enhanced in vivo and in culture, 2 ) ERK1/2 activation inhibits association of IRS-1 with p85 via IRS-1 Ser 312 phosphorylation, and 3 ) ERK1/2 activation may play a role in normal feedback of insulin signaling and contribute to resistance to insulin’s metabolic actions in PCOS. AMPK, AMP-activated protein kinase ERK, extracellular signal–regulated kinase FBS, fetal bovine serum IRS, insulin receptor substrate MAPK, mitogen-activated protein kinase MEK, mitogen-activated/extracellular signal–regulated kinase kinase PCOS, polycystic ovary syndrome PI, phosphatidylinositol Footnotes 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. A.C. and H.Z. contributed equally to this study. Accepted November 18, 2005. Received April 7, 2005. DIABETES