Myo1c Regulates Glucose Uptake in Mouse Skeletal Muscle

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 ϳ2-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.Glucose uptake in skeletal muscle provides energy for muscle fibers and is also critical in the maintenance of whole body glucose homeostasis. In people with type 2 diabetes, defects in insulin-stimulated glucose uptake in skeletal muscle are a major factor in impaired glucose homeostasis. Therefore, elucidating the molecular mechanisms regulating glucose uptake in muscle has been the focus of considerable research and could eventually lead to the development of new treatments for type 2 diabetes.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 (1-5). Glucose transporter 4 (GLUT4) is the major glucose transporter protein expressed in skeletal muscle, and in the basal state, it is contained in specialized intracellular vesicular structures. Insulin stimulates GLUT4 translocation in muscle via a distinct, well characterized intracellular signaling cascade that includes phosphorylation of the insulin receptor and insulin receptor substrate-1/2 (IRS-1/2), activation of phosphatidylinositol 3-kinase (PI3-kinase), and phosphorylation of Akt (6). Although the signaling pathways by which muscle con...

Myo1c regulates lipid raft recycling to control cell spreading, migration and Salmonella invasion

“…S1B). This specific phenotype was further verified by overexpressing a dominant-negative Myo1c variant (the 'rigor' mutant) in which the motor function is inhibited by a single point mutation (K111R) in the ATP-binding site (Aschenbrenner et al, 2004;Ruppel and Spudich, 1996;Toyoda et al, 2011). In cells expressing this non-functional Myo1c rigor mutant, caveolin-1 (Fig.…”

Calcium signaling in insulin action on striated muscle

“…Rab13 acts at the cell periphery potentially to promote GLUT4 vesicle tethering, docking or fusion [1,12]. Insertion of GLUT4 at the membrane requires prior tethering to actin filaments through the monomeric molecular motor Myosin 1c [9,35] and docking/fusion is enacted by the SNARE complex formed by VAMP2 on GLUT4 vesicles [36] and SNAP23 and syntaxin 4 on the plasma membrane [37,38]. Thus, this signal transduction relay impacts directly on the intracellular traffic machinery to mobilize GLUT4 vesicles to the muscle cell plasma membrane, where glucose uptake is consequently enhanced.…”

“…Excised skeletal muscle and muscle fibers, as well as cultured primary cardiomyocytes and differentiated skeletal myotubes, constitute ideal study systems to analyze insulin action on glucose uptake as they all respond to the hormone with a rapid increase in glucose uptake mediated by GLUT4 translocation to the cell surface [1][2][3][4][5][6][7][8][9][10][11][12]. Notably, GLUT4 translocation and the insulin-derived signals regulating this process fail during insulin resistance, a condition that leads to the development of type 2 diabetes mellitus in humans.…”

Molecular motor MYO1C, acetyltransferase KAT6B and osteogenetic transcription factor RUNX2 expression in human masseter muscle contributes to development of malocclusion

“…12 Isoforms 1 and 2 of MYO1C regulate glucose uptake via facilitated glucose transporter 4 ( GLUT 4 ) in skeletal muscle by acting as a motor for movement of GLUT4 - stored vesicles to plasma membranes after stimulation with insulin and contraction. 13-15 In micro-array experiments we recently found that expression of GLUT4 is nearly 3× higher in masseter from open-bite compared to deep bite patients. 16 GLUT4 is expressed at higher levels in Type I, slow contracting fibers in human vastus lateralis muscle, but not in soleus or triceps brachii muscles.…”