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Chronic Kidney Disease Causes Defects in Signaling through the Insulin Receptor Substrate/Phosphatidylinositol 3-Kinase/Akt Pathway: Implications for Muscle Atrophy

James L. Bailey^*, Bin Zheng^*, Zhaoyong Hu, S. Russ Price^* and William E. Mitch

^* Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; and Renal Division, Department of Medicine, Baylor College of Medicine, Houston, Texas

Address correspondence to: Dr. James L. Bailey, Renal Division, Emory University School of Medicine, WMB 338, 1639 Pierce Drive, Atlanta, GA 30322. Phone: 404-727-2525; Fax: 404-727-3425; E-mail: james.l.bailey{at}emory.edu

Received for publication October 11, 2004. Accepted for publication February 20, 2006.

Complications of chronic kidney disease (CKD) include depressed responses to insulin/IGF-1 and accelerated muscle proteolysis as a result of activation of caspase-3 and the ubiquitin-proteasome system. Experimentally, proteolysis in muscle cells occurs when there is suppression of phosphatidylinositol 3-kinase (PI3-K) activity. Postreceptor signaling through the insulin receptor substrate (IRS)/PI3-K/Akt pathway was evaluated in muscles of acidotic, CKD and pair-fed control rats under physiologic conditions and in response to a dose of insulin that quickly stimulated the pathway. Basal IRS-1–associated PI3-K activity was suppressed by CKD; IRS-2–associated PI3-K activity was increased. The basal level of activated Akt in CKD muscles also was low, indicating that the higher IRS-2–associated PI3-K activity did not compensate for the reduced IRS-1–associated PI3-K activity. Insulin treatment overcame this abnormality. The low IRS-1–associated PI3-K activity in muscle was not due to a decrease in IRS-1 protein, but there was a higher amount of the PI3-K p85 subunit protein without a concomitant increase in the p110 catalytic subunit, offering a potential explanation for the lower IRS-1–associated PI3-K activity. Eliminating the acidosis of CKD partially corrected the decrease in basal IRS-1–associated PI3-K activity and protein degradation in muscle. It is concluded that in CKD, acidosis and an increase in the PI3-K p85 subunit are mechanisms that contribute to suppression of PI3-K activity in muscle, and this leads to accelerated muscle proteolysis.

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