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

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 CA...

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Bibliographic Details
Published in:Human molecular genetics 2008-06, Vol.17 (12), p.1855-1866
Main Authors: Huang, Yanchao, de Morrée, Antoine, van Remoortere, Alexandra, Bushby, Kate, Frants, Rune R., Dunnen, Johan Tden, van der Maarel, Silvère M.
Format: Article
Language:English
Subjects:
3T3 Cells
Animals
Biological and medical sciences
Calpain - metabolism
Cercopithecus aethiops
COS Cells
Down-Regulation
Dysferlin
Fundamental and applied biological sciences. Psychology
Genetics of eukaryotes. Biological and molecular evolution
Membrane Proteins - metabolism
Mice
Molecular and cellular biology
Multiprotein Complexes - metabolism
Muscle Proteins - metabolism
Muscle, Skeletal - metabolism
Muscular Dystrophies, Limb-Girdle - genetics
Muscular Dystrophies, Limb-Girdle - metabolism
Neoplasm Proteins - metabolism
Up-Regulation
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Summary: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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddn081