Résumé :
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Facioscapulohumeral muscular dystrophy is an autosomal dominant neuromuscular disorder that is not due to a classical mutation within a protein-coding gene. Instead, almost all FSHD patients carry a reduced number of tandem 3.3-kilobase repeat units, termed D4Z4, located on chromosome 4q35. By overexpressing FRG1 gene, we recently developed the animal model for FSHD. In dystrophic muscle of FSHD patients as well as in FRG1 transgenics we observed the aberrant splicing of the fast skeletal troponin T gene. Here we demonstrate that alternative splicing isoforms of this gene translates into aberrant protein isoforms that characterize the dystrophic muscle. We show that isolated muscles of FRG1 over-expressing mice develop less strength and this phenomenon is due to the specific weakness of fast-twitch muscle fibers, which also show a reduced ability to contract. We display that fast-twitch fibers bear an anomalous ratio between Myosin Heavy Chain and actin, and a reduced sensitivity to Ca2+ in tension development. We demonstrate that the substitution of the anomalous troponin complex with the wild-type proteins restores the normal sensitivity to calcium in dystrophic muscle fibers. Remarkably, substitution of the wild-type troponin complex with the one isolated from FRG1 muscle diminishes tension developed by normal muscle fibers. Collectively our studies show that aberrant splicing of the fast skeletal troponin T is a major determinant of the reduced calcium sensitivity observed in the contraction of FRG1 dystrophic muscle fibers and and affects their capacity of developing tension, thus providing a molecular explanation for muscle weakness, the major determinant of patients' disability.
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