Abstract

Contraction and insulin promote glucose uptake in skeletal muscle through GLUT4 translocation to cell surface membranes. Although the signaling mechanisms leading to GLUT4 translocation have been extensively studied in muscle, the cellular transport machinery is poorly understood. Myo1c is an actin-based motor protein implicated in GLUT4 translocation in adipocytes; however, the expression profile and role of Myo1c in skeletal muscle have not been investigated. Myo1c protein abundance was higher in more oxidative skeletal muscles and heart. Voluntary wheel exercise (4 weeks, 8.2 ± 0.8 km/day), which increased the oxidative profile of the triceps muscle, significantly increased Myo1c protein levels by ∼2-fold versus sedentary controls. In contrast, high fat feeding (9 weeks, 60% fat) significantly reduced Myo1c by 17% in tibialis anterior muscle. To study Myo1c regulation of glucose uptake, we expressed wild-type Myo1c or Myo1c mutated at the ATPase catalytic site (K111A-Myo1c) in mouse tibialis anterior muscles in vivo and assessed glucose uptake in vivo in the basal state, in response to 15 min of in situ contraction, and 15 min following maximal insulin injection (16.6 units/kg of body weight). Expression of wild-type Myo1c or K111A-Myo1c had no effect on basal glucose uptake. However, expression of wild-type Myo1c significantly increased contraction- and insulin-stimulated glucose uptake, whereas expression of K111A-Myo1c decreased both contraction-stimulated and insulin-stimulated glucose uptake. Neither wild-type nor K111A-Myo1c expression altered GLUT4 expression, and neither affected contraction- or insulin-stimulated signaling proteins. Myo1c is a novel mediator of both insulin-stimulated and contraction-stimulated glucose uptake in skeletal muscle.

Highlights

  • Contraction and insulin are the major physiological stimulators of glucose uptake in muscle, and both stimuli increase uptake by increasing the number of glucose transporter proteins at the sarcolemma and transverse tubules [1,2,3,4,5]

  • Actin and microtubule networks are the major components of the cytoskeleton and have been reported to play roles in Glucose transporter 4 (GLUT4) translocation in cultured 3T3-L1 adipocytes, whereas only the actin network has been shown to be involved in glucose uptake in rat skeletal muscle [13, 14]

  • Because muscles composed of a higher percentage of oxidative fibers have greater levels of GLUT4 and glucose transport when compared with muscles containing more glycolytic fiber types [32, 33], we hypothesized that oxidative muscles would express greater levels of Myo1c

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Summary

Introduction

Contraction and insulin are the major physiological stimulators of glucose uptake in muscle, and both stimuli increase uptake by increasing the number of glucose transporter proteins at the sarcolemma and transverse tubules [1,2,3,4,5]. Muscles overexpressing wild-type Myo1c exhibited a significant increase in maximal insulin-stimulated glucose uptake There was no difference in GLUT4 protein expression among muscles injected with empty vector or wild-type Myo1c constructs (Fig. 3A and supplemental Table S1).

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