The neuromuscular junction is a small, complex structure linking the nervous system to muscle fibers. A body of evidence suggests that degeneration of neuromuscular junctions is important in the age-related loss of muscle mass and strength leading to sarcopenia, though it remains unclear as to which mechanisms of aging are most important in causing this degeneration. Here, researchers provide a short overview of the problem and present thinking on therapeutic options to address it by provoking regeneration of lost structures and function.
The neuromuscular junction (NMJ) is an essential synaptic structure composed of motor neurons, skeletal muscles, and glial cells that orchestrate the critical process of muscle contraction. Degenerated NMJs exhibit smaller or fragmented endplates, partial denervation, reduced numbers of synaptic vesicles, abnormal presynaptic mitochondria, and dysfunctional perisynaptic Schwann cells.
Sarcopenia, a degenerative skeletal muscle disease characterized by the loss of muscle strength, muscle mass, and overall physical activity, is closely associated with aging. Although sarcopenia shares some pathological features with muscular dystrophy, the exact mechanisms underlying muscle weakness observed in aging populations are not fully understood. Aging muscles display a range of neural changes, including alterations in peripheral nerves and NMJs, which may initiate a cascade of muscle pathologies.
Aging negatively impacts axonal transport, thereby affecting the delivery of essential synaptic and energetic cargoes, and is accompanied by alterations in neurofilaments. NMJ changes such as axonal denervation, reinnervation, and remodeling are increasingly recognized as pivotal in the onset and progression of sarcopenia. Research in both animal models and human subjects has demonstrated age-related NMJ degradation with significant changes in synaptic transmission and a shift in the types of muscle fibers present. Interestingly, caloric restriction and exercise attenuated the alteration of NMJs by aging. These studies support the hypothesis that targeting NMJ pathology can be a viable therapeutic approach, as evidenced by the improvements in muscle weakness observed in sarcopenia models following NMJ intervention.
Regarding the assessment on whether these NMJ alterations are reversible, AAV-mediated gene therapy, which enhances the expression of NMJ proteins such as MuSK, Rapsyn, or Dok7, has improved NMJ structure and muscular function in models of muscular dystrophy and sarcopenia. These therapies are not yet ready for clinical trials. Glial cells, including perisynaptic Schwann cells and satellite cells, are proposed to play a crucial role in maintaining NMJs. Thus, developing therapies targeting these neurons and glial cells is essential, because focusing only on the NMJ may not achieve the best therapeutic outcomes. Owing to their multiple actions on NMJs and glial cells, supplementation with neurotrophic factors could be a promising approach.
Link: https://doi.org/10.4103/NRR.NRR-D-23-02055
View the full article at FightAging
