title: Calpain 3 is a modulator of the dysferlin protein complex in skeletal muscle.
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.
authors.affiliation: Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Yanchao
authors.initials: Y
authors.lastname: Huang
authors.forename: Antoine
authors.initials: A
authors.lastname: de Morrée
authors.forename: Alexandra
authors.initials: A
authors.lastname: van Remoortere
authors.forename: Kate
authors.initials: K
authors.lastname: Bushby
authors.forename: Rune R
authors.initials: RR
authors.lastname: Frants
authors.forename: Johan T
authors.initials: JT
authors.lastname: den Dunnen
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
mesh_terms: D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D002154:Calpain / Q000378:metabolism*; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D000073939:Dysferlin; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C075176:AHNAK protein, human; C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D009124:Muscle Proteins; D009363:Neoplasm Proteins; C105884:CAPN3 protein, human; D002154:Calpain