Enhanced mitogenic signaling in skeletal muscle of women with polycystic ovary syndrome

Anne Corbould, Haiyan Zhao, Salida Mirzoeva, Fraser Aird, Andrea Dunaif*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

114 Scopus citations

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 Ser312 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 Ser312 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.

Original languageEnglish (US)
Pages (from-to)751-759
Number of pages9
JournalDiabetes
Volume55
Issue number3
DOIs
StatePublished - Mar 2006

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Fingerprint Dive into the research topics of 'Enhanced mitogenic signaling in skeletal muscle of women with polycystic ovary syndrome'. Together they form a unique fingerprint.

Cite this