Electrical pulse stimulation induces differential responses in insulin action in myotubes from severely obese individuals

Abstract

Key points Exercise/exercise training can enhance insulin sensitivity through adaptations in skeletal muscle, the primary site of insulin‐mediated glucose disposal; however, in humans the range of improvement can vary substantially. The purpose of this study was to determine if obesity influences the magnitude of the exercise response in relation to improving insulin sensitivity in human skeletal muscle. Electrical pulse stimulation (EPS; 24 h) of primary human skeletal muscle myotubes improved insulin action in tissue from both lean and severely obese individuals, but responses to EPS were blunted with obesity. EPS improved insulin signal transduction in myotubes from lean but not severely obese subjects and increased AMP accumulation and AMPK Thr172 phosphorylation, but to a lesser degree in myotubes from the severely obese. These data reveal that myotubes of severely obese individuals enhance insulin action and stimulate exercise‐responsive molecules with contraction, but in a manner and magnitude that differs from lean subjects. Abstract Exercise/muscle contraction can enhance whole‐body insulin sensitivity; however, in humans the range of improvements can vary substantially. In order, to determine if obesity influences the magnitude of the exercise response, this study compared the effects of electrical pulse stimulation (EPS)‐induced contractile activity upon primary myotubes derived from lean and severely obese (BMI ≥ 40 kg/m2) women. Prior to muscle contraction, insulin action was compromised in myotubes from the severely obese as was evident from reduced insulin‐stimulated glycogen synthesis, glucose oxidation, glucose uptake, insulin signal transduction (IRS1, Akt, TBC1D4), and insulin‐stimulated GLUT4 translocation. EPS (24 h) increased AMP, IMP, AMPK Thr172 phosphorylation, PGC1α content, and insulin action in myotubes of both the lean and severely obese subjects. However, despite normalizing indices of insulin action to levels seen in the lean control (non‐EPS) condition, responses to EPS were blunted with obesity. EPS improved insulin signal transduction in myotubes from lean but not severely obese subjects and EPS increased AMP accumulation and AMPK Thr172 phosphorylation, but to a lesser degree in myotubes from the severely obese. These data reveal that myotubes of severely obese individuals enhance insulin action and stimulate exercise‐responsive molecules with contraction, but in a manner and magnitude that differs from lean subjects.

Roux-en-Y gastric bypass surgery restores insulin-mediated glucose partitioning and mitochondrial dynamics in primary myotubes from severely obese humans

“…29 Therefore, we cannot exclude the possible effects of increased physical activity on the improvements in mitochondrial dynamics and glucose metabolism in primary myotubes raised from RYGB patients. In fact, the similar improvements in myotubes derived from obese humans at the chronic stage after RYGB surgery (7-months) 10 and after exercise training 47,48 suggests that RYGB surgery-induced weight loss and exercise training may share the same mechanisms for improving intrinsic phenotypes of mitochondrial dynamics and glucose metabolism in skeletal muscle from obese humans.…”

Growth and differentiation factor 15 is secreted by skeletal muscle during exercise and promotes lipolysis in humans

“…EPS of human myotubes can be used to induce forced contraction and mimic exercise in vitro (28). Although some studies have used EPS to assess individual variability in biological response to exercise in vitro (29,30) and to identify a potentially novel secreted factors by skeletal muscle contraction (31-33), very few have investigated how closely EPS recapitulates the metabolic consequences of exercise. Here, we developed two exercise models: one acute high-intensity exercise model that recapitulates the expected physiological responses with strong glycogen depletion and high lactate production (34) and one chronic moderate exercise model that more closely mimics the biological adaptations of endurance exercise training with increased basal glycogen storage along with an upregulation of substrate oxidation rates (35).…”

The Lands cycle modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle

“…The glycogen synthesis rate was quantified as previously described (61, 62). Briefly, cells were incubated in media containing D-[U- 14 C] glucose with (12 nM) or without insulin for 2h at 37 °C.…”