Cycles of myofiber degeneration and regeneration lead to remodeling of the neuromuscular junction in two mammalian models of Duchenne muscular dystrophy.

Seth G Haddix,Wesley J Thompson,Young Il Lee,Joe N Kornegay,William D Phillips

doi:10.1371/journal.pone.0205926

Seth G Haddix, Wesley J Thompson + Show 3 more

Open Access

https://doi.org/10.1371/journal.pone.0205926

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Journal: PloS one	Publication Date: Oct 31, 2018
Citations: 39	License type: CC BY 4.0

Affiliation: Texas A&M University

Abstract

Mice lacking the sarcolemmal protein dystrophin, designated mdx, have been widely used as a model of Duchenne muscular dystrophy. Dystrophic mdx mice as they mature develop notable morphological abnormalities to their neuromuscular junctions, the peripheral cholinergic synapses responsible for activating muscle fibers. Most obviously the acetylcholine receptor aggregates are fragmented into small non-continuous, islands. This contrasts with wild type mice whose acetylcholine receptor aggregates are continuous and pretzel-shaped in appearance. We show here that these abnormalities in mdx mice are also present in a canine model of Duchenne muscular dystrophy and provide additional evidence to support the hypothesis that NMJ remodeling occurs due to myofiber degeneration and regeneration. Using a method to investigate synaptic AChR replacement, we show that neuromuscular junction remodeling in mdx animals is caused by muscle fiber degeneration and regeneration at the synaptic site and is mimicked by deliberate myofiber injury in wild type mice. Importantly, the innervating motor axon plays a crucial role in directing the remodeling of the neuromuscular junction in dystrophy, as has been recorded in aging and deliberate muscle fiber injury in wild type mice. The remodeling occurs repetitively through the life of the animal and the changes in junctions become greater with age.

Highlights

Duchene muscular dystrophy (DMD) is a fatal, X-linked recessive disease caused by a mutation in the gene encoding the protein dystrophin [1]
This study provides strong evidence that neuromuscular junction (NMJ) fragmentation in mdx muscles is initiated by bouts of myofiber degeneration and regeneration, and that the innervating motor axon terminal must be present during fiber regeneration to instruct NMJ remodeling
The morphological abnormalities that are evident in mouse mdx NMJs occur in the more clinically relevant canine Golden Retriever Muscular Dystrophy (GRMD) model and the same processes that instruct remodeling mice likely occur in GRMD

Summary

Introduction

Duchene muscular dystrophy (DMD) is a fatal, X-linked recessive disease caused by a mutation in the gene encoding the protein dystrophin [1]. Lost fibers are replaced with fibrotic and adipose tissue leading to muscle weakness and death Another proposed consequence of necrosis and regeneration in this disease is a gross morphological change to the neuromuscular junction (NMJ) as has been shown in aging and deliberately damaged muscles [9,10,11]. The NMJ is a peripheral synapse that includes the postsynaptic acetylcholine receptor (AChR) aggregate, the innervating motor axon, and the terminal Schwann cells (tSCs) that cap the synapse [12] It is responsible for elicitation of muscle contractions, so it is not surprising that changes are evident in models of DMD, which is a myopathy. If the innervating motor axon is not present remodeling does not occur even following muscle fiber regeneration

Materials and methods

Findings

Discussion