Exercise training prevents skeletal muscle plasma membrane cholesterol accumulation, cortical actin filament loss, and insulin resistance in C57BL/6J mice fed a western-style high-fat diet.

Ashley G Ambery,Lixuan Tackett,Joseph T Brozinick,Jeffrey S Elmendorf,Brent A Penque

doi:10.14814/phy2.13363

Abstract

Insulin action and glucose disposal are enhanced by exercise, yet the mechanisms involved remain imperfectly understood. While the causes of skeletal muscle insulin resistance also remain poorly understood, new evidence suggest excess plasma membrane (PM) cholesterol may contribute by damaging the cortical filamentous actin (F‐actin) structure essential for GLUT4 glucose transporter redistribution to the PM upon insulin stimulation. Here, we investigated whether PM cholesterol toxicity was mitigated by exercise. Male C57BL/6J mice were placed on low‐fat (LF, 10% kCal) or high‐fat (HF, 45% kCal) diets for a total of 8 weeks. During the last 3 weeks of this LF/HF diet intervention, all mice were familiarized with a treadmill for 1 week and then either sham‐exercised (0 m/min, 10% grade, 50 min) or exercised (13.5 m/min, 10% grade, 50 min) daily for 2 weeks. HF‐feeding induced a significant gain in body mass by 3 weeks. Sham or chronic exercise did not affect food consumption, water intake, or body mass gain. Prior to sham and chronic exercise, “pre‐intervention” glucose tolerance tests were performed on all animals and demonstrated that HF‐fed mice were glucose intolerant. While sham exercise did not affect glucose tolerance in the LF or HF mice, exercised mice showed an improvement in glucose tolerance. Muscle from sham‐exercised HF‐fed mice showed a significant increase in PM cholesterol, loss of cortical F‐actin, and decrease in insulin‐stimulated glucose transport compared to sham‐exercised LF‐fed mice. These HF‐fed skeletal muscle membrane/cytoskeletal abnormalities and insulin resistance were improved in exercised mice. These data reveal a new therapeutic aspect of exercise being regulation of skeletal muscle PM cholesterol homeostasis. Further studies on this mechanism of insulin resistance and the benefits of exercise on its prevention are needed.

Highlights

Insulin resistance starts years before type 2 diabetes (T2D) diagnosis, even before recognition of prediabetes (Mason et al 2007; Tabak et al 2009)
We have shown that insulinstimulated glucose disposal in mice, rats, swine, and humans is inversely related to plasma membrane (PM) cholesterol content (Habegger et al 2012a) and that normalization of PM cholesterol restores insulin responsivity (Bhonagiri et al 2011; Habegger et al 2012a,b)
We investigated whether excess PM cholesterol, which compromises cortical actin filaments essential for insulin-stimulated glucose transport, is improved by exercise

Summary

Introduction

Insulin resistance starts years before type 2 diabetes (T2D) diagnosis, even before recognition of prediabetes (Mason et al 2007; Tabak et al 2009). As enhanced skeletal muscle insulin-stimulated glucose transport following exercise results from, at least in part, increased sarcolemmal GLUT4 content (Hansen et al 1998; Geiger et al 2006), a defect in GLUT4 trafficking not coupled to proximal insulin signaling must be alleviated by exercise. Several possibilities exist including a residual effect of contraction-stimulated glucose transport This insulin-mimetic action of exercise is mostly reversed by ~2-3 h postexercise, whereas enhanced muscle insulin sensitivity, detectable at ~1-4 h postexercise, can persist for up to 24-48 h (Cartee 2015b). Given the lack of clarity on how skeletal muscle insulin sensitivity is improved after exercise, we tested the possibility that exercise improves membrane cholesterol and actin cytoskeletal aspects of GLUT4 regulation

Materials and Methods

Results

Discussion