Increased SRF transcriptional activity in human and mouse skeletal muscle is a signature of insulin resistance

J Clin Invest. 2011 Mar;121(3):918-29. doi: 10.1172/JCI41940.

Abstract

Insulin resistance in skeletal muscle is a key phenotype associated with type 2 diabetes (T2D) for which the molecular mediators remain unclear. We therefore conducted an expression analysis of human muscle biopsies from patients with T2D; normoglycemic but insulin-resistant subjects with a parental family history (FH(+)) of T2D; and family history-negative control individuals (FH(–)). Actin cytoskeleton genes regulated by serum response factor (SRF) and its coactivator megakaryoblastic leukemia 1 (MKL1) had increased expression in T2D and FH(+) groups. Furthermore, striated muscle activator of Rho signaling (STARS), an activator of SRF, was upregulated in T2D and FH(+) and was inversely correlated with insulin sensitivity. Skeletal muscle from insulin-resistant mice recapitulated this gene expression pattern and showed reduced G-actin and increased nuclear localization of MKL1, each of which regulates SRF activity. Overexpression of MKL1 or reduction in G-actin decreased insulin-stimulated Akt phosphorylation, whereas reduction of STARS expression increased insulin signaling and glucose uptake. Pharmacological SRF inhibition by CCG-1423 reduced nuclear MKL1 and improved glucose uptake and tolerance in insulin-resistant mice in vivo. Thus, SRF pathway alterations are linked to insulin resistance, may contribute to T2D pathogenesis, and could represent therapeutic targets.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actins / metabolism
  • Animals
  • Biopsy
  • Cohort Studies
  • Cytoskeleton / metabolism
  • Gene Expression Regulation*
  • Glucose / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Resistance
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / metabolism*
  • Phosphorylation
  • Rats
  • Serum Response Factor / metabolism*
  • Signal Transduction

Substances

  • Actins
  • Insulin
  • Serum Response Factor
  • Glucose