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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Calpain-1 is required for hydrogen peroxide-induced myotube atrophy

¹Exercise Biochemistry Laboratory and ²Muscle Physiology Laboratory, Department of Applied Physiology and Kinesiology, Center for Exercise Science, University of Florida, Gainesville, Florida

Submitted 1 October 2008 ; accepted in final form 17 December 2008

Recent reports suggest numerous roles for cysteine proteases in the progression of skeletal muscle atrophy due to disuse or disease. Nonetheless, a specific requirement for these proteases in the progression of skeletal muscle atrophy has not been demonstrated. Therefore, this investigation determined whether calpains or caspase-3 is required for oxidant-induced C2C12 myotube atrophy. We demonstrate that exposure to hydrogen peroxide (25 µM H₂O₂) induces myotube oxidative damage and atrophy, with no evidence of cell death. Twenty-four hours of exposure to H₂O₂ significantly reduced both myotube diameter and the abundance of numerous proteins, including myosin (–81%), -actinin (–40%), desmin (–79%), talin (–37%), and troponin I (–80%). Myotube atrophy was also characterized by increased cleavage of the cysteine protease substrate II-spectrin following 4 h and 24 h of H₂O₂ treatment. This degradation was blocked by administration of the protease inhibitor leupeptin (10 µM). Using small interfering RNA transfection of mature myotubes against the specific proteases calpain-1, calpain-2, and caspase-3, we demonstrated that calpain-1 is required for H₂O₂-induced myotube atrophy. Collectively, our data provide the first evidence for an absolute requirement for calpain-1 in the development of skeletal muscle myotube atrophy in response to oxidant-induced cellular stress.

skeletal muscle; protease; oxidative stress

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