AbstractTo clarify the involvement of calpains in sarcolemmal remodeling, we examined the expression of calpains and their substrate, α‐fodrin, in various disorders of muscle. Although immunohistological reactions for α‐fodrin and calpains were weak in normal control muscles, intense immunoreactivity for α‐fodrin at the sarcolemma and for calpains throughout the cytoplasm were detected in small muscle fibers from patients with inflammatory myositis (IM), rhabdomyolysis (Rhab), and Duchenne muscular dystrophy (DMD). Most of the calpain‐α‐fodrin double‐positive muscle fibers in IM and Rhab also expressed the developmental form of myosin heavy chain. The sarcolemma of these small muscle fibers reacted with an antibody that specifically recognizes the 150‐kDa fragments of α‐fodrin (SBDP 150s) cleaved by calpain, but not caspase 3. Western blot analysis confirmed these results. These observations indicate that calpain is activated and reacts with α‐fodrin as a substrate at the sarcolemma, and plays a key role in modulating sarcolemmal proteins to adapt to the specific conditions in each myopathy. Muscle Nerve, 2005