Adaptive Remodeling of the Neuromuscular Junction with Aging

Abstract

Aging is associated with gradual degeneration, in mass and function, of the neuromuscular system. This process, referred to as “sarcopenia”, is considered a disease by itself, and it has been linked to a number of other serious maladies such as type II diabetes, osteoporosis, arthritis, cardiovascular disease, and even dementia. While the molecular causes of sarcopenia remain to be fully elucidated, recent findings have implicated the neuromuscular junction (NMJ) as being an important locus in the development and progression of that malady. This synapse, which connects motor neurons to the muscle fibers that they innervate, has been found to degenerate with age, contributing both to senescent-related declines in muscle mass and function. The NMJ also shows plasticity in response to a number of neuromuscular diseases such as amyotrophic lateral sclerosis (ALS) and Lambert-Eaton myasthenic syndrome (LEMS). Here, the structural and functional degradation of the NMJ associated with aging and disease is described, along with the measures that might be taken to effectively mitigate, if not fully prevent, that degeneration.

The Effect of Metabolites on Mitochondrial Functions in the Pathogenesis of Skeletal Muscle Aging

“…70,71 Recent findings have implicated the neuromuscular junction to be an important locus in the development and progression of sarcopenia, while it is still unclear whether glutamate is involved in the adaptive remodeling of the neuromuscular junction in patients with sarcopenia. 72 Altogether, the current evidence supports that the change in glutamate metabolism level is one of the reasons for the decrease in muscle energy metabolism. However, whether glutamate can become a potential therapeutic product to improve the symptoms of sarcopenia remains a question for further research.…”

Slow or fast: Implications of myofibre type and associated differences for manifestation of neuromuscular disorders

“…268,269 Ageing has many adverse effects on NMJs, with consequences for sarcopenia and neurodegenerative diseases like ALS. 270 The changes during normal human age-related loss of muscle mass and function (i.e., sarcopenia) 7,271 correspond with changes during normal ageing of rodents. Transcriptome analyses identified early denervation of muscles associated with the onset and progression of sarcopenia in mice and rats from about 15 months of age, as well as changes in metabolism and ECM composition.…”

“…During normal ageing of the peripheral nervous system, there is increasing loss of motor units, axonal atrophy, demyelination caused by oxidative damage to proteins and lipids, and modified transmission of the electrical signal through the NMJ. 270,278 However, it remains unclear whether sarcopenia is initiated and driven primarily by changes in nerves or muscles. Though, neuronal differences contribute to manifestation of many specific neuromuscular disorders.…”

“…Fast NMJs, with larger synaptic depression from repetitive stimulation, 265 are specialised to resist this and ensure reliable transmission during prolonged stimulation through greater neurotransmitter release 265 and thus amplitude of the motor endplate potential, 263 increased density of acetylcholine receptors and voltage‐dependent sodium channels in the postsynaptic folds, 266,267 and greater acetylcholinesterase activity that removes neurotransmitter of the NMJ 268,269 . Ageing has many adverse effects on NMJs, with consequences for sarcopenia and neurodegenerative diseases like ALS 270 …”

Sarcopenia: Molecular regulatory network for loss of muscle mass and function

“…Deschenes et al ( 24 ) proposed that acetylcholine release increased in aged muscles leading to a faster rate of neuromuscular fatigue. It has been suggested that decreasing ACh may be an effective remedy to treat structural changes in NMJ that can lead to sarcopenia ( 25 ).…”