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This version published online on March 30, 2006
Endocrinology, doi:10.1210/en.2005-0382
A more recent version of this article appeared on July 1, 2006
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Submitted on April 1, 2005
Accepted on March 22, 2006

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

Danshan Huang, Michelle Khoe, Dusko Ilic, and Michael Bryer-Ash*

West Los Angeles Veterans Administration Medical Center and UCLA Gonda (Goldschmied) Diabetes Center, Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Stomatology and Anatomy, University of California, San Francisco, California. Present address: StemLifeLine, Inc., 1300 Industrial Road #13, San Carlos, California 94114, Tel: (650) 592-7838

* To whom correspondence should be addressed. 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 IRS-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 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.
Key words: glycogen synthesis • glucose transport • cytoskeleton • F-actin • antisense FAK




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