Effects of resveratrol and contractile activity in human skeletal muscle myotubes from severely obese individuals

Abstract

The prevalence of obesity is exponentially increasing worldwide. Although strategies such as exercise, nutritional intervention, and pharmaceutical therapies including resveratrol have been extensively studied in lean or obese individuals, the effects of those interventions in severe obesity remains unestablished. Moreover, metabolic responses to resveratrol supplementation and exercise intervention in severely obese individuals are unclear and controversial. To investigate this, primary human skeletal muscle myotubes from severely obese subjects (BMI [greater-than or equal to] 40 kg/m2) were isolated from muscle biopsies, and both resveratrol and contractile activity were examined. Specifically, 24 hours of resveratrol treatment (1 [micro]M) improved insulin-stimulated glycogen synthesis, an index of insulin sensitivity in cell culture, as well as glucose oxidation in the myotubes of severely obese individuals despite suppressed responses compared to lean counterparts. The molecular mechanism involved appeared to be an increased activation of AMPK phosphorylation in both subject groups while the mechanisms in lean subjects appeared to be an improvement in insulin signal transduction. Muscle contractile activity applied by an electrical stimulator for 24 hours increased insulin-stimulated glycogen synthesis and glucose oxidation in both groups, but the response was significantly suppressed in myotubes of the severely obese compared to lean individuals. These findings suggest a resistance to exercise. Intriguingly, contractile activity normalized insulin-stimulated glucose metabolism in severely obese subjects to the level seen in lean subjects under control conditions (non-electrical stimulation). The cellular mechanisms involved appeared to consist of glycogen depletion, increased accumulation of nucleotides, especially AMP, increased activation of AMPK and ACC and PGC1[alpha] protein content in both subject groups. When compared to severely obese subjects, lean subjects presented the higher responses of insulin-mediated glucose metabolism appeared to consist of greater accumulation of AMP, greater activation of AMPK phosphorylation, and increased protein expression of IRS1, Akt, and AS160 phosphorylation compared to severely obese subjects. The results from this study suggest that both resveratrol and contractile activity alter the inherent characteristics of human skeletal muscle in severely obese individuals, leading to improved insulin action although responses are dampened compared to lean subjects. The results indicate two intriguing factors in severely obese subjects: 1) both resveratrol and contractile activity are sufficient to improve insulin-mediated glucose metabolism similar or better than lean subjects with insulin alone, and 2) muscle stimulation can provide higher efficacy to increase insulin-induced glucose metabolism by almost 2 fold; however, resveratrol treatment exhibited approximately 1.3 fold increase over non-insulin and non-treatment condition in severely obese subjects. Collectively, the results of this study provide valuable functional and molecular mechanism in which resveratrol and muscle contractile activity can improve insulin action in skeletal muscle from severely obese individuals.