AbstractDefects in human calpain 3 are responsible for limb‐girdle muscular dystrophy type 2A, an autosomal‐recessive disorder characterized mainly by late‐onset proximal muscular atrophy. A corresponding murine model has previously been generated by gene targeting. In this report, muscular activity of calpain 3–deficient (capn3−/−) mice was evaluated at different ages. Growth curves showed a progressive global muscular atrophy. Histological examination throughout the lifespan of mice confirmed the dystrophic lesions. Whole animal tests showed only a mild significant impairment of the forelimbs. Studies of the mechanical properties of selected isolated fast‐ and slow‐twitch muscles demonstrated that slow‐twitch muscles were significantly weaker in capn3−/− mice than in wild‐type mice. Three different tests showed that there was no membrane disruption, suggesting a nonmechanical etiology of capn3−/− mice dystrophy. These findings are consistent with a mechanism involving signaling systems. Muscle Nerve 27: 616–623, 2003