This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hu, J. Articles by Wang, X. H. Search for Related Content PubMed PubMed Citation Articles by Hu, J. Articles by Wang, X. H.

Cardiac Muscle Protein Catabolism in Diabetes Mellitus: Activation of the Ubiquitin-Proteasome System by Insulin Deficiency

Renal Division (J.H., J.D.K., X.H.W.), Department of Medicine, Emory University, Atlanta, Georgia 30322; and Nephrology Division (J.D.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Dr. Xiaonan Wang, Emory University School of Medicine, Renal Division, 1639 Pierce Drive, NE, WMB Room 338, M/S 1930/001/1AG, Atlanta, Georgia 30322. E-mail: xwang03{at}emory.edu.

Protein degradation is increased by both insulin deficiency and insulin resistance in humans and animal models. In skeletal muscle this insulin-dependent increase in protein degradation involves activation of both caspase-3 and the ubiquitin-proteasome system. The influence of abnormal insulin signaling on protein metabolism in cardiac muscle is not well understood; therefore, we measured protein degradation in cardiac muscle of mice with streptozotocin-induced diabetes. Insulin deficiency increased both total muscle proteolysis (measured as tyrosine release in muscle slices or extracts) and the degradation of the myofibrillar protein actin (measured as the appearance of a 14-kDa actin fragment). Expression of ubiquitin mRNA and chymotrypsin-like activity in the proteasome were increased, indicating activation of the ubiquitin-proteasome system in diabetic mouse heart. We also evaluated possible signaling pathways that might regulate cardiac muscle proteolysis. Insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and Akt phosphorylation were decreased. Insulin replacement prevented the decrease in IRS-1/Akt phosphorylation, the increase in proteolysis, and attenuated the increase in ubiquitin mRNA. We conclude that insulinopenia accelerates proteolysis in cardiac muscle by reducing IRS-1/Akt signaling, which leads to activation of the ubiquitin-proteasome proteolytic pathway.

This article has been cited by other articles:

				H. Su and X. Wang The ubiquitin-proteasome system in cardiac proteinopathy: a quality control perspective Cardiovasc Res, September 16, 2009; (2009) cvp287v2. [Abstract] [Full Text] [PDF]