1. Academic Validation
  2. Increased SRF transcriptional activity in human and mouse skeletal muscle is a signature of insulin resistance

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.
Wanzhu Jin 1 Allison B Goldfine Tanner Boes Robert R Henry Theodore P Ciaraldi Eun-Young Kim Merve Emecan Connor Fitzpatrick Anish Sen Ankit Shah Edward Mun Vokes Vokes Joshua Schroeder Elizabeth Tatro Jose Jimenez-Chillaron Mary-Elizabeth Patti
Affiliations

Affiliation

  • 1 Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, Massachusetts, USA.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-13991
    99.94%, Rho/MRTF/SRF Pathway Inhibitor