Lindqvist J, Levy Y, Pati-Alam A, et al. Modulating myosin restores muscle function in a mouse model of nemaline myopathy. Ann Neurol 2016;79:717-725.
Submitted by Andrew W. Tarulli, MD, News Science Editorial Board
Nemaline myopathy is among the most common of the congenital myopathies. Approximately 20% of cases are caused by mutations in the ACTA1 gene which disrupts actin-myosin interactions and prevents effective cross-bridging. In this study, Lindqvist and colleagues generated a knock-in mouse model expressing the ACTA1 mutation, and identified muscle atrophy in these mice at 8 weeks. In the second part of the experiment, they injected intramuscularly an adeno-associated viral vector (AAV) with a myosin light chain 4 (MYL4) transgene into both transgenic and wild type mice. The transgene encodes MyLC1a/emb, a myosin isoform present only in embryo heart and skeletal muscles, and is capable of generating greater force than normal adult myosin. Injections were performed when the mice reached 4 weeks of age. When the transgene was injected into ACTA1 transgenic mice, there was an increase in both myofiber size and in isometric maximal force-producing capacity when compared with those mice injected with a control vector. Furthermore, wild type mice showed an increase in contractility when injected with the MYL4 transgene.
: The authors demonstrated increased myofiber size and force generation in myocytes of ACTA1 transgenic mice injected with the gene encoding the MyLC1a/emb isoform. The injections were performed four weeks prior to the anticipated myocyte atrophy. A next logical next step, therefore, would be to perform the injections after myocyte atrophy has already been identified, a strategy that would more closely parallel potential human applications. The authors hypothesize that the MYL4 transgene might also be applied to nemaline myopathy caused by gene defects in other contractile proteins. Because wild type mice also demonstrated an increase in contractility, gene therapy with this MYL4 transgene could be effective for muscle disorders other than the nemaline myopathies.
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