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 allelicdisorders caused by mutations in the C-terminus of titin, a giant sarcomeric protein. Both clinical presentationswere initially identified in a large Finnish family and linked to a founder mutation (FINmaj). To furtherunderstand the physiopathology of these two diseases, we generated a mouse model carrying the FINmajmutation. In heterozygous mice, dystrophic myopathology appears late at 9 months of age in few distalmuscles. In homozygous (HO) mice, the first signs appear in the Soleus at 1 month of age and extend tomost muscles at 6 months of age. Interestingly, the heart is also severely affected in HO mice. The mutationleads to the loss of the very C-terminal end of titin and to a secondary deficiency of calpain 3, a partner oftitin. 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.