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PTEN expression contributes to the regulation of muscle protein degradation in diabetes

Nephrology Division, Baylor College of Medicine, Houston, TX
* Renal Division, Emory University School of Medicine, Atlanta, GA
** Departments of Surgery, Indiana University School of Medicine, Indianapolis, IN

Correspondence: zhaoyonh{at}bcm.edu

Objective:Conditions accelerating muscle proteolysis are frequently associated with defective phosphatidylinositol 3-kinase (PI3K)/Akt signaling and reduced PI3K-generated PIP3 (phosphatidylinositol [3,4,5] triphosphate). We evaluated the control of muscle protein synthesis and degradation in mouse models of type 1 and 2 diabetes to determine if defects besides PI3K/Akt activities affect muscle metabolism.

Research Design and Methods:We evaluated the expression and activity of PTEN, the phosphatase converting PIP3 to inactive PIP2 and studied how PTEN influences muscle protein in diabetic wild type mice and mice with partial deficiency of PTEN(+/-).

Results:In acutely diabetic mice, muscle PTEN expression was decreased. It was increased by chronic diabetes or insulin resistance. In cultured C2C12 myotubes, acute suppression of PI3K activity led to decreased PTEN expression while palmitic acid increased PTEN in myotubes in a p38-dependent fashion. To examine if PTEN affects muscle protein turnover, we studied primary myotubes cultures from wild-type and PTEN(+/-) mice. The proteolysis induced by serum deprivation was suppressed in PTEN(+/-) cells. Moreover, the sizes of muscle fibers in PTEN(+/-) mice and wild-type mice were similar but, the increase in muscle proteolysis caused by acute diabetes was significantly suppressed by PTEN(-/+). This anti-proteolytic response involved higher PIP3 and p-Akt levels and a decrease in caspase-3-mediated actin cleavage and activation of the ubiquitin-proteasome system as signified by reduced induction of Atrogin-1/MAFbx or MurF1 indicating.

Conclusions:Changes in PTEN expression participate in the regulation of muscle proteolytic pathways. A decrease in PTEN could be a compensatory mechanism to prevent muscle protein losses.

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