Résumé :
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Titin is a giant protein expressed in both skeletal muscles and heart. Titin spans from the Z-disc to the M-line of striated muscle sarcomeres. Several pathogenic mutations were identified in its last two exons causing the phenotype of late onset Tibialis Muscular Dystrophy (TMD). The most common mutation, FINmaj, results in the replacement of 4 amino acids and affects TMD patients in Finland. The disease course is relatively mild with selective atrophy of the tibialis anterior in the early stages. When present on both alleles, the clinical manifestations are completely different and far more severe with progressive atrophy and dystrophy of the girdle muscles leading to wheelchair confinement: this Limb Girdle Muscular Dystrophy phenotype is known as LGMD2J. In addition, the expression of calpain 3, a protease responsible for LGMD2A when mutated, is greatly reduced in LGMD2J muscles, In order to study the physiopathology of these two diseases and to test therapeutic approaches, a mouse model reproducing the FINmaj mutation was created. Although heterozygous and homozygous animals have a normal life span, abnormalities in the transmission ratio suggest a partial embryonic lethality Whereas the phenotype seems very mild in heterozygous, gait is affected in homozygous animals, possibly reflecting muscle force impairment. In line with this hypothesis, the force of the soleus is reduced. Soleus, tibialis and psoas are indeed severely affected: muscle fibres show signs of inflammation and atrophy, necrosis-regeneration and fibrosis. As seen in LGMD2J, calpain 3 protein level is reduced in heterozygous and homozygous mice, probably related to protein destabilisation because of impaired titin interaction As a conclusion, this model reproduces symptoms of the human LGMD2J and will therefore be valuable, not only to test therapeutic strategies, but also to document the functional relationship between titin and calpain 3 and other molecular pathways involved in c-terminal titin pathology.
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