Rac1 Is a Novel Regulator of Contraction-Stimulated Glucose Uptake in Skeletal Muscle

  1. Erik A. Richter1
  1. 1Molecular Physiology Group, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
  2. 2Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
  3. 3Institute of Sports Medicine, Department of Orthopedic Surgery, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
  4. 4Clinical Pharmacology Diabetes, Novo Nordisk A/S, Søborg, Denmark
  5. 5Department of Biomedical Sciences, Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark
  1. Corresponding author: Erik A. Richter, erichter{at}ifi.ku.dk.

Abstract

In skeletal muscle, the actin cytoskeleton-regulating GTPase, Rac1, is necessary for insulin-dependent GLUT4 translocation. Muscle contraction increases glucose transport and represents an alternative signaling pathway to insulin. Whether Rac1 is activated by muscle contraction and regulates contraction-induced glucose uptake is unknown. Therefore, we studied the effects of in vivo exercise and ex vivo muscle contractions on Rac1 signaling and its regulatory role in glucose uptake in mice and humans. Muscle Rac1-GTP binding was increased after exercise in mice (∼60–100%) and humans (∼40%), and this activation was AMP-activated protein kinase independent. Rac1 inhibition reduced contraction-stimulated glucose uptake in mouse muscle by 55% in soleus and by 20–58% in extensor digitorum longus (EDL; P < 0.01). In agreement, the contraction-stimulated increment in glucose uptake was decreased by 27% (P = 0.1) and 40% (P < 0.05) in soleus and EDL muscles, respectively, of muscle-specific inducible Rac1 knockout mice. Furthermore, depolymerization of the actin cytoskeleton decreased contraction-stimulated glucose uptake by 100% and 62% (P < 0.01) in soleus and EDL muscles, respectively. These are the first data to show that Rac1 is activated during muscle contraction in murine and human skeletal muscle and suggest that Rac1 and possibly the actin cytoskeleton are novel regulators of contraction-stimulated glucose uptake.

Footnotes

  • Received April 19, 2012.
  • Accepted November 7, 2012.

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  1. Diabetes vol. 62 no. 4 1139-1151
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