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Am J Physiol Endocrinol Metab (July 31, 2007). doi:10.1152/ajpendo.00045.2007
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Submitted on January 17, 2007
Accepted on July 29, 2007

Nitric Oxide Increases GLUT4 Expression and Regulates AMPK Signaling in Skeletal Muscle

Vitor A Lira1, Quinlyn A Soltow1, Jodi HD Long1, Jenna L Betters1, Jeff E Sellman1, and David S. Criswell1*

1 Applied Physiology & Kinesiology, University of Florida, Gainesville, Florida, United States

* To whom correspondence should be addressed. E-mail: dcriswell{at}hhp.ufl.edu.

Nitric oxide (NO) and 5'-AMP-activated protein kinase (AMPK) are involved in glucose transport and mitochondrial biogenesis in skeletal muscle. Here, we examined whether NO regulates the expression of the major glucose transporter in muscle (GLUT4), and whether it influences AMPK-induced upregulation of GLUT4. At low levels, the NO-donor, SNAP (1 and 10µM), significantly increased GLUT4 mRNA (~3-fold; P<0.05) in L6 myotubes, and co-treatment with the AMPK inhibitor, Compound C, ablated this effect. The cGMP analog 8-Br-cGMP (2mM) increased GLUT4 mRNA by ~50% (P<0.05). GLUT4 protein expression was elevated 40% by 2d treatment with 8-Br-cGMP, whereas 6d treatment with 10µM SNAP increased GLUT4 expression by 65%. Co-treatment of cultures with the guanylyl cyclase inhibitor, ODQ, prevented the SNAP-induced increase in GLUT4 protein. 10µM SNAP also induced significant phosphorylation of {alpha}AMPK, ACC and translocation of p-{alpha}AMPK to the nucleus. Further, L6 myotubes exposed to 5-aminoimidazole-4-carboxamide-1-{beta}-D-ribofuranoside (AICAR) for 16 hours presented an ~9-fold increase in GLUT4 mRNA, whereas co-treatment with the non-isoform specific NOS inhibitor, N(G)-L-nitro-arginine methyl ester (L-NAME), prevented ~70% of this effect. In vivo, GLUT4 mRNA was increased 1.8-fold in the rat plantaris muscle 12h after AICAR injection, and this induction was reduced by ~50% in animals co-treated with the nNOS and iNOS selective inhibitor, 1-(2-trifluoromethyl-phenyl)-imidazole (TRIM). We conclude that in skeletal muscle NO increases GLUT4 expression via a cGMP- and AMPK-dependent mechanism. The data are consistent with a role for NO in the regulation of AMPK, possibly via control of cellular activity of AMPK kinases and/or AMPK phosphatases.




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