Key result
Lmod3-deficient mice display severe muscle weakness, postnatal growth retardation, nemaline bodies, and fast-myofiber-specific atrophy, providing a novel model for nemaline myopathy.
Lmod3 deficiency in mice causes nemaline myopathy with fast-myofiber-specific atrophy, providing a novel mammalian model for studying myopathy pathogenesis.
Provides novel preclinical model for nemaline myopathy; leaves open human translation and therapeutic relevance.
Nemaline myopathy (NM) is one of the most common forms of congenital myopathy, and affects either fast myofibers, slow myofibers, or both. However, an animal model for congenital myopathy with fast-myofiber-specific atrophy is not available. Furthermore, mutations in the leiomodin-3 (LMOD3) gene have recently been identified in a group of individuals with NM. However, it is not clear how loss of LMOD3 leads to NM. Here, we report a mouse mutant in which the piggyBac (PB) transposon is inserted into the Lmod3 gene and disrupts its expression. Lmod3(PB/PB) mice show severe muscle weakness and postnatal growth retardation. Electron microscopy and immunofluorescence studies of the mutant skeletal muscles revealed the presence of nemaline bodies, a hallmark of NM, and disorganized sarcomeric structures. Interestingly, Lmod3 deficiency caused muscle atrophy specific to the fast fibers. Together, our results show that Lmod3 is required in the fast fibers for sarcomere integrity, and this study offers the first NM mouse model with muscle atrophy that is specific to fast fibers. This model could be a valuable resource for interrogating myopathy pathogenesis and developing therapeutics for NM as well as other pathophysiological conditions with preferential atrophy of fast fibers, including cancer cachexia and sarcopenia.
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Tian et al. (2015) studied Nemaline myopathy. Lmod3 gene disruption vs. Wild-type or heterozygous Lmod3 mice was evaluated on Muscle phenotype including growth, strength, and histology. Lmod3-deficient mice display severe muscle weakness, postnatal growth retardation, nemaline bodies, and fast-myofiber-specific atrophy, providing a novel model for nemaline myopathy.
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