The Neuromuscular Junction: Roles in Aging and Neuromuscular Disease

Abstract

The neuromuscular junction (NMJ) is a specialized synapse that bridges the motor neuron and the skeletal muscle fiber and is crucial for conversion of electrical impulses originating in the motor neuron to action potentials in the muscle fiber. The consideration of contributing factors to skeletal muscle injury, muscular dystrophy and sarcopenia cannot be restricted only to processes intrinsic to the muscle, as data show that these conditions incur denervation-like findings, such as fragmented NMJ morphology and corresponding functional changes in neuromuscular transmission. Primary defects in the NMJ also influence functional loss in motor neuron disease, congenital myasthenic syndromes and myasthenia gravis, resulting in skeletal muscle weakness and heightened fatigue. Such findings underscore the role that the NMJ plays in neuromuscular performance. Regardless of cause or effect, functional denervation is now an accepted consequence of sarcopenia and muscle disease. In this short review, we provide an overview of the pathologic etiology, symptoms, and therapeutic strategies related to the NMJ. In particular, we examine the role of the NMJ as a disease modifier and a potential therapeutic target in neuromuscular injury and disease.

Keywords: NMJ; exercise; muscular dystrophy; myasthenia gravis; sarcopenia.

Figure 1

The neuromuscular junction (NMJ) in skeletal muscle. (A) Representative electron microscopy image showing ultrastructure of the NMJ. (B) Representative confocal microscopy image of fluorescent stain with an acetylcholine receptor binding neurotoxin (α-Bungarotoxin, BTX, red). (C) Illustration describing the components of the NMJ. Perisynaptic Schwann cells are glial regulators of NMJ structure and function. Agrin interacts with lipoprotein receptor-related protein 4 (Lrp4), which activates muscle-specific kinase (MuSK). MuSK, a transmembrane tyrosine kinase, through signaling of Dok-7 and rapsyn, drives acetylcholine receptor (AChR) clustering. Dystrophin and its associated glycoprotein complex (DGC), which is present throughout the muscle fiber membrane, accumulate underneath the post-synaptic membrane.

Figure 2

The neuromuscular junction (NMJ) as a central node in neuromuscular function. There are many conditions in which the NMJ plays a critical role or at least as a mediator of disease (red). However, some interventions can minimize NMJ dysfunction (green). LEMS: Lambert-Eaton Myasthenic Syndrome.