Neuromuscular junction degeneration in muscle wasting

Abstract

Purpose of review Denervation is a hallmark of age-related and other types of muscle wasting. This review focuses on recent insights and current viewpoints regarding the mechanisms and clinical relevance of maintaining the neuromuscular junction to counteract muscle wasting resulting from aging or neural disease/damage. Recent findings Activity-dependent regulation of autophagy, the agrin-MuSK-Lrp4 signaling axis, and sympathetic modulation are principal mechanisms involved in stabilizing the neuromuscular junction. These findings are derived from several animal models and were largely confirmed by human gene expression analysis as well as insights from rare neuromuscular diseases such as amyotrophic lateral sclerosis and congenital myasthenic syndromes. Based on these insights, agrin-derived fragments are currently being evaluated as biomarkers for age-related muscle wasting. Tuning of autophagy, of the agrin pathway, and of sympathetic input are being studied as clinical treatment of muscle wasting disorders. Summary Basic research has revealed that maintenance of neuromuscular junctions and a few signaling pathways are important in the context of age-dependent and other forms of muscle wasting. These findings have recently started to enter clinical practice, but further research needs to substantiate and refine our knowledge.

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

“…These models explore different mechanisms and have been described in recent reviews. 7,292 Potential therapies to combat the age-related deficits in skeletal muscle function There is significant academic and commercial interest in the development of therapies, of both pharmacological and nonpharmacological origin, to combat the loss of skeletal muscle mass and function, in the context of neuromuscular ageing and a wide range of myopathies. 293 Physical activity is one of the most effective interventions known to delay the progression of several aspects of muscle ageing.…”

Neuromuscular junctions are stable in patients with cancer cachexia

“…Although the majority of research to date has focused on muscle abnormalities as the major locus of pathophysiology in cachexia, many lines of evidence have implicated the neuromuscular junction (NMJ) as a critical and early mediator of neuromuscular dysfunction and breakdown. Principally, NMJ dysfunction and denervation represent a shared hallmark of several related muscle-wasting conditions and neuromuscular diseases (7)(8)(9). For example, NMJ pathology is considered to represent a key early driver of neuromuscular defects in age-related sarcopenia (10)(11)(12), at least in part the result of an age-related loss of motor neurons (13).…”

Postnatal Development and Distribution of Sympathetic Innervation in Mouse Skeletal Muscle

“…This was different in the most recent study, which used optical tissue clearing in combination with reporter mice expressing a fluorescent protein under dopamine beta-hydroxylase promoter control and which showed axons different to those of lower motor neurons approaching the NMJs [ 4 ]. Additional recent work argues in favor of an important role of sympathetic innervation for muscle trophic status [ 15 ] and in the context of CMS [ 1 , 16 , 17 ] and other neuromuscular diseases including spinal muscular atrophies and amyotrophic lateral sclerosis [ 18 ]. Thus, the sympathetic innervation of muscle, and of NMJs in particular, is a new field of research and nothing is known so far about its developmental aspects.…”