Calpain 3 is a modulator of the dysferlin protein complex in skeletal muscle

Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Human Molecular Genetics (Impact Factor: 6.68). 07/2008; 17(12):1855-66. DOI: 10.1093/hmg/ddn081
Source: PubMed

ABSTRACT Muscular dystrophies comprise a genetically heterogeneous group of degenerative muscle disorders characterized by progressive muscle wasting and weakness. Two forms of limb-girdle muscular dystrophy, 2A and 2B, are caused by mutations in calpain 3 (CAPN3) and dysferlin (DYSF), respectively. While CAPN3 may be involved in sarcomere remodeling, DYSF is proposed to play a role in membrane repair. The coexistence of CAPN3 and AHNAK, a protein involved in subsarcolemmal cytoarchitecture and membrane repair, in the dysferlin protein complex and the presence of proteolytic cleavage fragments of AHNAK in skeletal muscle led us to investigate whether AHNAK can act as substrate for CAPN3. We here demonstrate that AHNAK is cleaved by CAPN3 and show that AHNAK is lost in cells expressing active CAPN3. Conversely, AHNAK accumulates when calpain 3 is defective in skeletal muscle of calpainopathy patients. Moreover, we demonstrate that AHNAK fragments cleaved by CAPN3 have lost their affinity for dysferlin. Thus, our findings suggest interconnectivity between both diseases by revealing a novel physiological role for CAPN3 in regulating the dysferlin protein complex.

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Available from: Antoine de Morree, Dec 16, 2014
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    • "Furthermore, ahnak has been identified as a constituent of the dysferlin protein complex that is important for sarcolemmal integrity (Huang et al. 2007, 2008; de Morree et al. 2010). Interestingly, the interaction between ahnak1 and dysferlin is lost after proteolytic processing of ahnak1 by calpain3 (Huang et al. 2008). Because of the complex interactions between ahnak1, dysferlin, and calpain3 and their role in muscle repair and regeneration we compared ahnak1 expression in patients with LGMD2B and LGMD2A. "
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