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.

Adaptive Remodeling of the Neuromuscular Junction with Aging

“…This suggests that more vesicles are released with the arrival of an action potential at presynaptic nerve-terminal endings, or that the quantal size—the amount of ACh stored per vesicle—is amplified with aging. Since the EPP, an indirect measure of quantal size, has been reported to be greater among aged NMJs, at least some of the gain in quantal content, or the amount of neurotransmitter released on stimulation, must be attributed to an increased quantal size or greater ACh per vesicle [ 14 , 50 , 85 ]. This increased quantal size is evident in data revealing that the total amount of ACh at nerve terminal endings is less among aged, than it is among young, adult NMJs [ 86 , 87 , 88 ].…”

“…Yet, despite this exaggerated fragmentation, when these diaphragm muscles were assessed for neuromuscular transmission, no age-related differences were detected. That notwithstanding, an even more recent review of this topic asserts that disruption in the structure of the NMJ in aged muscles is indeed coupled with significant disturbances in their function [ 14 , 48 , 85 ].…”

“…This is a fatal neurodegenerative disease that is usually detected in the eighth decade of life and is conventionally believed to originate in the motor neurons of the central nervous system (CNS) before proceeding to the skeletal muscle in an anterograde manner. However, more recently, it has been suggested that this disease may first manifest itself at the NMJ and propagate in a retrograde manner along the motor neurons’ axons in a “dying back” direction [ 12 , 13 , 14 , 15 , 16 , 17 ]. What is clearly known, however, is that the NMJ is affected by ALS, resulting in weakening and wasting of the skeletal muscle [ 12 , 13 , 14 ].…”

“…However, more recently, it has been suggested that this disease may first manifest itself at the NMJ and propagate in a retrograde manner along the motor neurons’ axons in a “dying back” direction [ 12 , 13 , 14 , 15 , 16 , 17 ]. What is clearly known, however, is that the NMJ is affected by ALS, resulting in weakening and wasting of the skeletal muscle [ 12 , 13 , 14 ].…”

Skeletal Muscle Denervation: Past, Present and Future

“…Skeletal muscle innervation comprises stable and functional nerve interactions with muscles via neuromuscular junctions (NMJ). It is critical for the maintenance of normal muscle structure and function [ 1 ]. Loss of motor innervation induces rapid skeletal muscle fiber degeneration with the activation of atrophy-related signaling and subsequent disassembly of the sarcomeres [ 2 ].…”