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.
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Karine Charton, Nathalie Danièle, Anna Vihola, Carinne Roudaut, Evelyne Gicquel, et al.. Removal of the calpain 3 protease reverses the myopathology in a mouse model for titinopathies. Human Molecular Genetics, Oxford University Press (OUP), 2010, 19 (23), pp.4608-4624. ⟨10.1093/hmg/ddq388⟩. ⟨hal-02321460⟩

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