Recovery of altered neuromuscular junction morphology and muscle function in mdx mice after injury.

Stephen J P Pratt,Jaclyn P Kerr,Sameer B Shah,Christopher W Ward,Joseph P Stains,Richard M Lovering

doi:10.1007/s00018-014-1663-7

Abstract

Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease in which weakness, increased susceptibility to muscle injury, and inadequate repair underlie the pathology. While most attention has focused within the muscle fiber, we recently demonstrated significant alterations in the neuromuscular junction (NMJ) morphology and resulting neuromuscular transmission failure (NTF) 24 h after injury in mdx mice (murine model for DMD). Here we determine the contribution of NMJ morphology and NTF to the recovery of muscle contractile function post-injury. NMJ morphology and NTF rates were assessed day 0 (immediately after injury) and days 1, 7, 14 and 21 after quadriceps injury. Eccentric injury of the quadriceps resulted in a significant loss of maximal torque in both WT (39 ± 6 %) and mdx (76 ± 8 %) with a full recovery in WT by day 7 and in mdx by day 21. Post-injury alterations in NMJ morphology and NTF were found only in mdx, were limited to days 0 and 1, and were independent of changes in MuSK or AChR expression. Such early changes at the NMJ after injury are consistent with mechanical disruption rather than newly forming NMJs. Furthermore, we show that the dense microtubule network that underlies the NMJ is significantly reduced and disorganized in mdx compared to WT. These structural changes at the NMJ may play a role in the increased NMJ disruption and the exaggerated loss of nerve-evoked muscle force seen after injury to dystrophic muscles.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-014-1663-7) contains supplementary material, which is available to authorized users.

Highlights

We show that the dense microtubule network that underlies the neuromuscular junction (NMJ) is significantly reduced and disorganized in mdx compared to WT
The most common and severe form of muscular dystrophy is Duchenne muscular dystrophy (DMD), a disorder caused by the absence of dystrophin, a structural protein found on the cytoplasmic surface of the sarcolemma
Proper development and organization at the NMJ is necessary for effective neuromuscular transmission [3, 4], but a number of pathological conditions affecting the distribution of acetylcholine receptors (AChRs) can lead to a reduction in the safety factor and impairment of neuromuscular transmission [2]

Summary

Introduction

The most common and severe form of muscular dystrophy is Duchenne muscular dystrophy (DMD), a disorder caused by the absence of dystrophin, a structural protein found on the cytoplasmic surface of the sarcolemma. The DGC accumulates at the postsynaptic membrane (aka motor end-plate) of the neuromuscular junction (NMJ), the area of synaptic contact between a motor neuron and its target muscle fiber. Neuromuscular transmission is normally highly reliable, as each nerve impulse results in the release of more neurotransmitter (acetylcholine) than is required for evoking an action potential in the muscle fiber. This release of ‘surplus’ transmitter and consequent ‘excess’ depolarization of the postsynaptic membrane via acetylcholine receptors (AChRs), often referred to as the ‘safety factor’ [2], ensures that a muscle contraction will occur in response to each nerve impulse, at least in healthy tissue. Proper development and organization at the NMJ is necessary for effective neuromuscular transmission [3, 4], but a number of pathological conditions affecting the distribution of AChRs can lead to a reduction in the safety factor and impairment of neuromuscular transmission [2]

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