Impairment Mechanisms and Intervention Approaches for Aged Human Neuromuscular Junctions

Abstract

The neuromuscular junction (NMJ) is a chemical synapse formed between a presynaptic motor neuron and a postsynaptic muscle cell. NMJs in most vertebrate species share many essential features; however, some differences distinguish human NMJs from others. This review will describe the pre- and postsynaptic structures of human NMJs and compare them to NMJs of laboratory animals. We will focus on age-dependent declines in function and changes in the structure of human NMJs. Furthermore, we will describe insights into the aging process revealed from mouse models of accelerated aging. In addition, we will compare aging phenotypes to other human pathologies that cause impairments of pre- and postsynaptic structures at NMJs. Finally, we will discuss potential intervention approaches for attenuating age-related NMJ dysfunction and sarcopenia in humans.

Keywords: active zone (AZ); aging; caloric restriction; exercise; laminin; neuromuscular disease; progeria; synapse.

FIGURE 1

Comparison between human and mouse neuromuscular junctions. Schematic diagrams show (A) human versus (B) mouse NMJs based on nerve-specific stains (adapted from Jones et al., 2017). The NMJ size and axon diameter are significantly smaller in humans compared to mice. Scale bar, 10 μm. A diagram depicting an active zone at the (C) human and (D) mouse NMJs. In mice, muscle-derived synapse organizer laminin β2 interacts with presynaptic voltage-gated calcium channels (VGCC) to organize active zones (Nishimune et al., 2004). Super-resolution microscopy revealed the nanoscale localization of the SNARE protein synaptosomal associated protein-25 (SNAP25) in human and mouse NMJs (Jones et al., 2017), active zone-specific proteins, and acetylcholine receptors (AChR) in mice (Nishimune et al., 2016; York and Zheng, 2017), which are described in bold italic characters. The nanoscale localization of active zone-specific proteins and acetylcholine receptors in human NMJs has not been revealed yet.