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Submitted on April 10, 2006
Accepted on September 27, 2006
Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, Australia; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia; School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, Australia
* To whom correspondence should be addressed. E-mail: M.Cleasby{at}garvan.org.au.
The PI3-kinase/Akt pathway is thought to be essential for normal insulin action and glucose metabolism in skeletal muscle and has shown to be dysregulated in insulin resistance. However, the specific roles of and signaling pathways triggered by Akt isoforms have not been fully assessed in muscle in vivo. We over-expressed constitutively active (ca-) Akt-1 or Akt-2 constructs in muscle using in vivo electrotransfer and after one week assessed the roles of each isoform on glucose metabolism and fiber growth. We achieved greater than 2.5-fold increases in total Ser473 phosphorylation in muscles expressing ca-Akt-1 and ca-Akt-2 respectively. Both isoforms caused hypertrophy of muscle fibers, consistent with increases in p70S6kinase phosphorylation, and a 60% increase in glycogen accumulation, although only Akt-1 increased glycogen synthase kinase-3
phosphorylation. Akt-2 but not Akt-1 increased basal glucose uptake (by 33%, P = 0.004) and incorporation into glycogen and lipids, suggesting a specific effect on glucose transport. Consistent with this short hairpin (sh)RNA-mediated silencing of Akt-2 caused reductions in glycogen storage and glucose uptake. Consistent with Akt-mediated IRS-1 degradation we observed c.30% reductions in IRS-1 protein in muscle over-expressing ca-Akt-1 or ca-Akt-2. Despite this we observed no decrease in insulin-stimulated glucose uptake. Furthermore a 68% reduction in IRS-1 levels induced using shRNAs targeting IRS-1 also did not affect glucose disposal after a glucose load. These data indicate distinct roles for Akt-1 and Akt-2 in muscle glucose metabolism and that moderate reductions in IRS-1 expression does not result in the development of insulin resistance in skeletal muscle in vivo.
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