Insulin resistance in skeletal muscle is a prominent feature of obesity and type 2 diabetes. The molecular mechanisms involved in insulin resistance remain elusive. Evidence has begun to emerge to hint that the extracellular matrix (ECM) and the structure and function of muscle itself may be involved in the pathogenesis of insulin resistance. The aim of this study was to determine promoter DNA methylation of mechanosignaling genes of the ECM, cytoskeletal and mitochondria in insulin resistant skeletal muscle.
Vastus lateralis muscle biopsies were taken during a euglycemic-hyperinsulinemic clamp, and reduced representation bisulfite sequencing was performed on muscle DNA from obese insulin resistant (n=10; BMI=32.9±0.7 kg/m2; glucose disposal rate=4.5±0.7 mg/kg/min) and lean insulin sensitive (n=12; BMI=23.4±0.7 kg/m2; glucose disposal rate=7.3±0.6 mg/kg/min) participants.
We showed decreased methylation in collagen genes (COL18A1: -28.2%, COL6A2: -18.5%, COL5A3: -15.6%, COL2A1: -10.1%, COL6A3: -5.0%, all P<0.05) in insulin resistant muscle. There was a significant increased methylation of the dystrophin (DMD: +25.2%) and spectrin, beta (SPTB: +24.5%) in insulin resistant muscle, both P<0.001. We showed increased methylation in alpha actinin 2 (ACTN2: +11.1%) and PDZ and LIM domain protein 1 and 7 (PDLIM1: +5.9%, PDLIM7: +3.6%) in insulin resistant muscle, all P<0.05. There was an increased methylation in a number of complex I nuclear encoded mitochondrial genes (NDUFA13: +15.2%, NDUFA3: +16.6%, NDUFA11: +32.0%) in insulin resistant muscle consistent with our previous findings of lower expression of these genes/proteins.
Our results provide evidence of altered methylation in mechanosignaling genes in insulin resistant muscle. We propose that the reduced response of insulin action in muscle of obese and type 2 diabetic participants is due, in part, to epigenetic modifications of the ECM-cytoskeletal-mitochondria mechanosignaling genes.