Abstract
Nemaline myopathies are heterogeneous congenital muscle disorders causing skeletal muscle weakness and, in some cases, death soon after birth. Mutations in nebulin, encoding a large sarcomeric protein required for thin filament function, are responsible for approximately 50% of nemaline myopathy cases. Despite the severity of the disease there is no effective treatment for nemaline myopathy with limited research to develop potential therapies. Several supplements, including L-tyrosine, have been suggested to be beneficial and consequently self-administered by nemaline myopathy patients without any knowledge of their efficacy. We have characterized a zebrafish model for nemaline myopathy caused by a mutation in nebulin. These fish form electron-dense nemaline bodies and display reduced muscle function akin to the phenotypes observed in nemaline myopathy patients. We have utilized our zebrafish model to test and evaluate four treatments currently self-administered by nemaline myopathy patients to determine their ability to increase skeletal muscle function. Analysis of muscle pathology and locomotion following treatment with L-tyrosine, L-carnitine, taurine, or creatine revealed no significant improvement in skeletal muscle function emphasizing the urgency to develop effective therapies for nemaline myopathy.
Highlights
Nemaline myopathies are congenital muscle diseases characterized by the presence of nemaline bodies that form within the skeletal muscles
The lack of an effective treatment for nemaline myopathy has resulted in many patients and their families testing compounds on an ad-hoc basis, with a number of compounds listed on patient support websites
We have established a zebrafish model of NEB nemaline myopathy to test the ability of existing supplements, currently self-administered by patients, to improve skeletal muscle function
Summary
Nemaline myopathies are congenital muscle diseases characterized by the presence of nemaline (rod-like) bodies that form within the skeletal muscles. Following L-tyrosine treatment, all patients reported varying short-term improvements in muscle strength and ‘energy’ levels, due to various limitations (no placebo group, large age variability, and variable disease mutations), no firm conclusions could be made as to efficacy [33]. L-tyrosine doses were administered to a mouse model of nemaline myopathy (ACTA1H40Y) for 4 weeks, and treatment was reported to partially alleviate mobility deficits and decrease nemaline bodies [26], the long-term benefits of L-tyrosine supplementation were not determined. We have established a zebrafish model of NEB nemaline myopathy to test the ability of existing supplements, currently self-administered by patients, to improve skeletal muscle function. The NEB nemaline myopathy model display decreased muscle function which cannot be improved by treatment by L-tyrosine, taurine, L-carnitine, or creatine. This suggests that existing treatments are ineffective in improving skeletal muscle performance in NEB nemaline myopathy, highlights the need for further research into novel therapies, and provides a model to assist in their identification
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