Leiomodin-3-deficient mice display nemaline myopathy with fast-myofiber atrophy.

Ling Sun,Sheng Ding,Tong-Ruei Li,Yun You,Lei Tian,Tian Xu,Xiaohui Wu,Yan Liu

doi:10.1242/dmm.019430

Ling Sun, Sheng Ding + Show 6 more

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https://doi.org/10.1242/dmm.019430

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Abstract

ABSTRACTNemaline 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. Lmod3PB/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.

Highlights

Nemaline myopathy (NM) accounts for 17% of cases of congenital myopathy, with an estimated incidence of 1 in 50,000 individuals (Maggi et al, 2013; Wallgren-Pettersson, 1990)
Our study shows that Lmod3-deficient mice display NM and offers the first mouse model for congenital myopathy with fast-myofiber atrophy
In the present study, the authors describe a mouse mutant in which the piggyBac (PB) transposon is inserted into the Lmod3 gene to disrupt its expression

Summary

Introduction

Nemaline myopathy (NM) accounts for 17% of cases of congenital myopathy, with an estimated incidence of 1 in 50,000 individuals (Maggi et al, 2013; Wallgren-Pettersson, 1990). The characteristic features of NM include muscle weakness and the presence of rodlike structures (nemaline bodies) in skeletal muscle fibers (North et al, 1997). Preferential atrophy of fast fibers is a common feature of other myopathy conditions, including cancer cachexia (Mendell and Engel, 1971) and sarcopenia (Lexell, 1995). The characteristic features of NM include muscle weakness and the presence of rod-like structures (nemaline bodies) in skeletal muscle fibers. The type of myofiber showing atrophy in individuals with NM varies from fast or slow fibers alone to both. Preferential atrophy of fast fibers is a common feature of other myopathy conditions, including cancer cachexia and other aging- or drug-induced myopathies. No therapy is available to treat NM or other forms of fast-fiber atrophy

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