AChRs Degeneration at NMJ in Aging-Associated Sarcopenia–A Systematic Review

Abstract

Sarcopenia is an aging process with a decline of skeletal muscle mass and function, which is a challenging public health problem with reduced quality of life in patients. The endplate, the post-synaptic part of the neuromuscular junction (NMJ), occupies 0.1% of the myofiber surface area only, but is composed of millions of acetylcholine receptors (AChRs) that are efficient in binding to acetylcholine (ACh) and triggering skeletal muscle contraction. This systematic review aims to examine aging-associated alterations of post-synaptic AChRs, including morphology, function and related gene expression. A systematic literature search was conducted in PubMed, Embase and Web of Science with relevant keywords by two independent reviewers. Original pre-clinical and clinical studies regarding AChRs changes during aging with available full text and written in English were included. Information was extracted from the included studies for further review. In total, 30 articles were included. Various parameters assessing AChRs alterations by radioassay, immunofluorescence, electrophysiology and mechanical test were reported. Endplate fragmentation and denervation were common in old skeletal muscles during aging. To ensure efficient NMJ transmission and force generation, type I or IIb muscle fibers tended to have increased ACh quanta releasing after electrical stimulations, while type IIa muscle fibers tended to have stronger binding between ACh and AChRs, but the overall function of AChRs was reduced during aging. Alterations of AChRs area depended on muscle type, species and the progress of muscle atrophy and type I muscles fibers tended to demonstrate enlarging AChRs areas. Myogenic regulator factors (MRFs) can regulate the expression of AChRs subunits, while decreased MRF4 may lead to expression changes of AChRs subunits during aging. Sarcoglycan-α can delay low-density lipoprotein receptor-related protein 4 (LRP4) degradation. This protein was increased in old muscles but still cannot suppress the degradation of LRP4. Investigating the role of these AChRs-related genes in the process of aging may provide a potential target to treat sarcopenia.

Age-Related Alterations at Neuromuscular Junction: Role of Oxidative Stress and Epigenetic Modifications

“…It has been reported by Klitgaard et al that co-expression of different isoforms of MHC in a single muscle fiber increases with age, suggesting a continuous shift in the type of muscle fiber [ 15 ], and it is demonstrated that muscles in elderly individuals contain more slow muscle fibers that reduce contraction ability [ 16 ]. This also supports endplate fragmentation and functional denervation [ 17 ].…”

Advanced Glycation End-Products in Skeletal Muscle Aging

“…Endplate fragmentation is a multi-stage disassociation of the NMJ typically seen during aging. This process is marked by a dispersal of clustered AChRs, AChR type switching, and increased turnover rates of the receptor [ 118 , 119 ]. As a way to compensate for fragmentation, increased enzyme levels of acetylcholinesterase and increased levels of acetylcholine (ACh) release from the synaptic terminal were detected [ 119 ].…”

Juvenile Neuromuscular Systems Show Amplified Disturbance to Muscle Unloading

“…Age-related disruptions in the structure and function of the NMJ, which enables communication between the nervous and skeletal muscle systems, have also been described ( Badawi and Nishimune, 2018 ; Dobrowolny et al, 2021 ; Fuertes-Alvarez and Izeta, 2021 ; Pratt et al, 2021 ). Age-related plasticity of the NMJ include fragmentation of the post-synaptic endplate, as well as increased length and branch points of pre-synaptic nerve terminal endings ( Deschenes et al, 2016 , 2018 ; Bao et al, 2020 ), with greater dispersion, and a smaller number of acetylcholine (ACh) containing pre-synaptic vesicles ( Petralia et al, 2014 ; Ivannikov and Van Remmen, 2015 ; Badawi and Nishimune, 2018 ). Numerous reports have also indicated that compared to young ones, aged neuromuscular systems are more vulnerable to the detrimental effects of disuse ( Robbins, 1992 ; Pandya and Patani, 2021 ), suggesting that at times of enhanced natural neuromuscular plasticity, imposed neuromuscular disuse elicits more pronounced morphological and physiological remodeling than during the mature, adult phase of life that comprises much of the lifespan ( Fahim, 1989 ; Deschenes and Wilson, 2003 ; Wilson and Deschenes, 2005 ).…”