title: Removal of the calpain 3 protease reverses the myopathology in a mouse model for titinopathies.
abstract: The dominant tibial muscular dystrophy (TMD) and recessive limb-girdle muscular dystrophy 2J are allelic disorders caused by mutations in the C-terminus of titin, a giant sarcomeric protein. Both clinical presentations were initially identified in a large Finnish family and linked to a founder mutation (FINmaj). To further understand the physiopathology of these two diseases, we generated a mouse model carrying the FINmaj mutation. In heterozygous mice, dystrophic myopathology appears late at 9 months of age in few distal muscles. In homozygous (HO) mice, the first signs appear in the Soleus at 1 month of age and extend to most muscles at 6 months of age. Interestingly, the heart is also severely affected in HO mice. The mutation leads to the loss of the very C-terminal end of titin and to a secondary deficiency of calpain 3, a partner of titin. By crossing the FINmaj model with a calpain 3-deficient model, the TMD phenotype was corrected, demonstrating a participation of calpain 3 in the pathogenesis of this disease.
authors.affiliation: Genethon, CNRS UMR8587 LAMBE, 1 rue de l’Internationale, Evry, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Charton
authors.forename: Nathalie
authors.initials: N
authors.lastname: Danièle
authors.forename: Anna
authors.initials: A
authors.lastname: Vihola
authors.forename: Carinne
authors.initials: C
authors.lastname: Roudaut
authors.forename: Evelyne
authors.initials: E
authors.lastname: Gicquel
authors.forename: François
authors.initials: F
authors.lastname: Monjaret
authors.forename: Anne
authors.initials: A
authors.lastname: Tarrade
authors.forename: Jaakko
authors.initials: J
authors.lastname: Sarparanta
authors.forename: Bjarne
authors.initials: B
authors.lastname: Udd
authors.forename: Isabelle
authors.initials: I
authors.lastname: Richard
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002154:Calpain / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D064211:Connectin; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D049310:Distal Myopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004452:Echocardiography; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D051379:Mice; D008854:Microscopy, Electron; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D016133:Polymerase Chain Reaction; D011494:Protein Kinases / Q000235:genetics; D012518:Sarcomeres / Q000235:genetics / Q000648:ultrastructure
chemical_list: D064211:Connectin; D009124:Muscle Proteins; D011494:Protein Kinases; D002154:Calpain; C491373:Capn3 protein, mouse