Oxidative Stress Impairs Skeletal Muscle Repair in Diabetic Rats

Oxidative Stress Impairs Skeletal Muscle Repair in Diabetic Rats Manuela Aragno 1 , Raffaella Mastrocola 1 , Maria Graziella Catalano 2 , Enrico Brignardello 2 , Oliviero Danni 1 and Giuseppe Boccuzzi 2 1 Department of Experimental Medicine and Oncology, University of Turin, Turin, Italy 2 Department of Clinical Pathophysiology, University of Turin, Turin, Italy Address correspondence and reprint requests to Prof. Giuseppe Boccuzzi, Department of Clinical Pathophysiology, Via Genova 3, University of Turin, 10126 Turin, Italy. E-mail: giuseppe.boccuzzi{at}unito.it Abstract Alongside increased proteolysis, the inability to repair damaged skeletal muscle is a characteristic feature of uncontrolled diabetes. This study evaluates the role of oxidative stress in muscle-specific gene regulatory regions and myosin chain synthesis in streptozotocin (STZ)-induced diabetic and ZDF rats. In the gastrocnemius muscle of diabetic rats, prooxidant compounds were seen to increase while antioxidant levels fell. Myogenic regulatory factors—Myo, myogenin, and Jun D—were also reduced, and muscle enhancer factor (MEF)-1 DNA binding activity was impaired. Moreover, synthesis of muscle creatine kinase and both heavy and light chains of myosin were impaired, suggesting that oxidative stress triggers the cascade of events that leads to impaired muscle repair. Dehydroepiandrosterone has been reported to possess antioxidant properties. When it was administered to diabetic rats, in addition to an improved oxidative imbalance there was a recovery of myogenic factors, MEF-1 DNA binding activity, synthesis of muscle creatine kinase, and myosin light and heavy chains. Vitamin E administration to STZ-induced diabetic rats reverses oxidative imbalance and improves muscle gene transcription, reinforcing the suggestion that oxidative stress may play a role in diabetes-related impaired muscle repair. CYC, cyclophilin DHEA, dehydroepiandrosterone HNE, hydroxynonenal MCK, myosin creatine kinase MEF, muscle enhancer factor MHC, myosin heavy chain MLC, myosin light chain MRF, myogenic regulatory factor STZ, streptozotocin TNF, tumor necrosis factor Footnotes Accepted January 13, 2004. Received July 14, 2003. DIABETES