Calpains, skeletal muscle function and exercise

Summary 1. Skeletal muscle fibres contain ubiquitous (μ‐calpain and m‐calpain) and muscle‐specific (calpain‐3) Ca 2+ ‐dependent proteases. The physiological roles of the calpains are not well understood, although ubiquitous calpains have been associated with apoptosis and myogenesis and calpain‐3 is likely involved in sarcomeric remodelling. A defect in the expression of calpain‐3 results in limb‐girdle muscular dystrophy Type 2A. 2. At resting [Ca 2+ ] i , calpains are present predominantly in their full‐length, unautolysed/unactivated forms. Once activated, μ‐calpain and calpain‐3 appear in their autolysed forms and this measurement can be used to determine when in vivo activation occurs. Endogenously expressed μ‐calpain and calpain‐3 are activated within a physiological [Ca 2+ ] range in a Ca 2+ ‐ and time‐dependent manner. 3. In skeletal muscle, μ‐calpain is a freely diffusible protein that binds rapidly when [Ca 2+ ] i is increased. Calpain‐3 is tightly bound in skeletal muscle fibres at the N2A line of the large elastic protein titin. 4. Overall, neither μ‐calpain nor calpain‐3 are activated immediately following sprint, endurance or eccentric exercise, despite the frequent episodes of high cytoplasmic [Ca 2+ ] that would occur during these types of muscle contractions. Importantly, however, a substantial proportion of calpain‐3, but not μ‐calpain, is activated 24 h after a single bout of eccentric exercise. 5. In vitro studies have shown that calpain‐3 becomes activated if exposed for a prolonged period of time (> 1 h) to resting cytoplasmic [Ca 2+ ] that are approximately two‐ to fourfold higher than normal. This suggests that the small but sustained increase in [Ca 2+ ] i that likely occurs after eccentric contractions is both high and long enough to result in calpain‐3 activation and supports the role for calpain‐3 in sarcomeric remodelling.