Sex-specific increases in myostatin and SMAD3 contribute to obesity-related insulin resistance in human skeletal muscle and primary human myotubes

Abstract

The purpose of the present study was to determine the effects of obesity and biological sex on myostatin expression in humans, and to examine the direct effects of myostatin, SMAD2 and SMAD3 on insulin signaling in primary human skeletal muscle cells (HSkMCs). Cohort 1: Fifteen lean (BMI: 22.1 ± 0.5 kg/m2, n=8 males, n=7 females) and fourteen obese (BMI: 40.6 ± 1.4 kg/m2, n=7 males, n=7 females) individuals underwent skeletal muscle biopsies and an oral glucose tolerance test (OGTT). Cohort 2: Fifteen young lean (BMI: 22.4 ± 1.9 kg/m2, n=6 males, n=8 females) and fourteen obese (BMI: 39.3 ± 7.9 kg/m2, n=6 males, n=8 females) individuals underwent muscle biopsies for primary HSkMC experiments. Plasma mature myostatin (P=0.041), skeletal muscle precursor myostatin (P=0.048) and skeletal muscle SMAD3 (P=0.029) were elevated in obese females compared to lean females, and plasma mature myostatin (r=0.58, P=0.029) and skeletal muscle SMAD3 (r=0.56, P=0.037) were associated with insulin resistance in females, but not males. Twenty-four hours of myostatin treatment impaired insulin signaling in primary HSkMC derived from females (P<0.024) but not males. Overexpression of SMAD3, but not SMAD2, impaired insulin-stimulated AS160 phosphorylation in HSkMC derived from lean females (-27%, P=0.040); whereas silencing SMAD3, improved insulin-stimulated AS160 phosphorylation and insulin-stimulated glucose uptake (25%, P<0.014) in HSkMC derived from obese females. These results suggest for the first time that myostatin-induced impairments in skeletal muscle insulin signaling are sex-specific and that increased body fat in females is associated with detrimental elevations in myostatin and SMAD3, which contribute to obesity-related insulin resistance.