Low dystrophin levels are insufficient to normalize the neuromuscular synaptic abnormalities of mdx mice

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Abstract

Dystrophin is a sub-sarcolemmal component of skeletal muscle fibres and is enriched at the postsynaptic membrane of the neuromuscular junction (NMJ). In the mdx mouse, dystrophin absence not only causes muscle damage but also mild synaptic dysfunctions and clear morphological aberrations at NMJs. In particular, reduction of postsynaptic sensitivity for the neurotransmitter acetylcholine and extra exhaustion of presynaptic acetylcholine release during intense synaptic activity exists. Current experimental therapeutic approaches in Duchenne muscular dystrophy aim to restore dystrophin expression. An important question is what dystrophin levels are needed to improve muscle function. Recent experimental and clinical studies suggested that levels as low as a few percent of normal can be beneficial. Similarly, it is of interest to know how dystrophin levels relate to NMJ function and morphology. We investigated NMJs of a series of mdx-XistΔhs mice, which expressed dystrophin between ~2% and 19% of normal. Most functional and morphological NMJ parameters of these mice remained comparable to mdx. On the other hand, mdx+/- mice (expressing ~50% dystrophin) showed normal NMJ features. Thus, the minimal dystrophin level required for normal NMJ function and morphology lies between 19% and 50% of normal when expression of dystrophin is not uniform.

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van der Pijl, E. M., van Putten, M., Niks, E. H., Verschuuren, J. J. G. M., Aartsma-Rus, A., & Plomp, J. J. (2018). Low dystrophin levels are insufficient to normalize the neuromuscular synaptic abnormalities of mdx mice. Neuromuscular Disorders, 28(5), 427–442. https://doi.org/10.1016/j.nmd.2018.02.013

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