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Reduced Expression of Focal Adhesion Kinase Disrupts Insulin Action in Skeletal Muscle Cells

West Los Angeles Veterans Administration Medical Center and UCLA Gonda (Goldschmied) Diabetes Center (D.H., M.K., M.B.), Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California 90095; and Department of Stomatology and Anatomy (D.I.), University of California, San Francisco, California 94143

Address all correspondence and requests for reprints to: Michael Bryer-Ash, M.D., UCLA Division of Endocrinology, Diabetes and Hypertension; 900 Veteran Avenue, Warren Hall Room 24-130; Los Angeles, California 90095. E-mail: mbryerash{at}mednet.ucla.edu.

Integrins mediate interactions between cells and extracellular matrix proteins that modulate growth factor signaling. Focal adhesion kinase (FAK) is a key multifunctional integrin pathway protein. We recently reported that disruption of FAK impairs insulin-mediated glycogen synthesis in hepatocytes. To test the hypothesis that FAK regulates skeletal muscle insulin action, we reduced FAK expression in L6 myotubes using FAK antisense. In untransfected myotubes, insulin stimulated both FAK tyrosine phosphorylation and kinase activity. Cells treated with antisense FAK showed 78 and 53% reductions in FAK mRNA and FAK protein, respectively, whereas insulin receptor substrate 1/2 and paxillin abundance were unaffected. Insulin-stimulated U-¹⁴C-glucose incorporation into glycogen was abolished by FAK antisense, and 2-deoxy-glucose uptake and glucose transporter 4 (GLUT4) translocation were both markedly attenuated. Antisense FAK did not alter GLUT1 or GLUT3 protein abundance. Immunofluorescence staining showed decreased FAK Tyr³⁹⁷ phosphorylation and reduced actin stress fibers. Thus, in skeletal myotubes, FAK regulates the insulin-mediated cytoskeletal rearrangement essential for normal glucose transport and glycogen synthesis. Integrin signaling may play an important regulatory role in muscle insulin action.

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