A Focus on the Neuromuscular Junction in Muscle Aging

Neuromuscular junctions link the nervous system with muscle tissue, allowing control of muscle activity. Muscle mass and strength decreases with age, condition known as sarcopenia. This is a process that can be turned back to some degree by strength training, even in late life, but ultimately leads to frailty. Muscle isn't just a mechanical tissue, it also has important metabolic roles relevant to the regulation of immune system activity, inflammation, and more.

There are many viewpoints on which of the mechanisms of sarcopenia are likely the most important, the best targets for intervention. For example, leucine processing is less effective in aged tissues, and supplementation with leucine is an easy intervention to test. The results in human trials are largely positive, but certainly not spectacular. Stem cell function and chronic inflammation are thought to be important, but reliable and broadly available approaches to address these issues are somewhat lacking.

A sizable contingent in the research community sees sarcopenia as primarily a neuromuscular issue. The neuromuscular junctions become damaged and dysfunctional, and the consequent lack of signaling into muscle tissue leads to declining muscle tissue maintenance and function. As is usually the case for age-related conditions, coming to a definitive answer on the importance of this mechanism, relative to all of the others, would require a way to repair and restore neuromuscular junctions to a youthful level of function without affecting other aspects of aging. Here also, viable approaches are presently lacking.

The Neuromuscular Junction: Roles in Aging and Neuromuscular Disease

Adult skeletal muscles decline in size with age, resulting in a loss of muscle mass (sarcopenia) and consequent weakness. The impact of muscle loss is exacerbated by the corresponding decline in the quality of the preserved muscle (e.g., amount of force per unit volume). These deficits, together with increased susceptibility to injury, reduced recovery, and proprioceptive decline, predispose the risk of falls and related injuries, which are linked to morbidity and mortality. Sarcopenia has enormous social and economic benefits: a 10% reduction in prevalence alone would result in savings of well over a billion dollars. Despite significant advances in understanding the molecular alterations in aging, the pathophysiology of age-associated muscle weakness remains unclear.

Some describe sarcopenia as a primary muscular pathology, with only minimal changes in the peripheral nerves and motor units occurring much later than the onset of sarcopenia. Indeed, aging muscles share several similarities to muscle dystrophies. Synaptic nuclei in aged muscle have abnormal expression of nuclear proteins, such as reduced LMNA gene expression, suggesting that muscle dysfunction with aging may be similar to that seen in laminopathies. Other similarities between aging muscle and dystrophic muscle include a loss of dystrophin with age. However, there is no consensus on other components of the dystrophin glycoprotein complex (DGC), with reports of increased, decreased and unchanged expression of DGC components.

However, the diminished muscle quality suggests additional neural contributions of to muscle wasting. A number of age-associated pathological changes have been reported in peripheral nerves and neuromuscular junctions (NMJs), which have even been posited to initiate and drive the muscle pathology in sarcopenia. There are strong correlations between aging and deficits in axonal transport in peripheral neurons. These deficits impair the delivery of vital synaptic and energetic cargoes to the pre-synaptic terminal and occur concurrent with age-associated changes in the neuronal cytoskeleton. Neurofilaments, the primary structural components of motor neurons and a key regulator of axonal caliber and cytoskeletal transport, appear particularly susceptible to age, based on observed changes in their density, organization, and phosphorylation state in aged mice.

Just as the NMJ dictates muscle physiology, it also influences muscle pathology. Several lines of evidence suggest that age-related changes in the NMJ play a key role in musculoskeletal impairment with aging. Indeed there is increasing consensus that functional muscle denervation is a principal factor leading to sarcopenia, and some even describe sarcopenia primarily as a "disorder of the NMJ". Despite the continuing ambiguity of sarcopenia etiology, it is clear that, at a minimum, age-dependent changes in the peripheral nerve and NMJ contribute to the muscle pathology in sarcopenia.