Cardiac muscle protein catabolism in diabetes mellitus: activation of the ubiquitin-proteasome system by insulin deficiency.
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.
Hu
Junping
J
Renal Division, Department of Medicine, Emory University, Atlanta, Georgia 30322, USA.
Klein
Janet D
JD
Du
Jie
J
Wang
Xiaonan H
XH
D000818:Animals; D020169:Caspases / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007328:Insulin / Q000172:deficiency* / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000378:metabolism / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology; D013311:Streptozocin; D025801:Ubiquitin / Q000378:metabolism*
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D009124:Muscle Proteins; D025801:Ubiquitin; D013311:Streptozocin; D051058:Oncogene Protein v-akt; D020169:Caspases; D046988:Proteasome Endopeptidase Complex