Reviewing Age-Related Changes in the Neuromuscular Junction

Synapses of the neuromuscular junction (NMJ) connect nerves to muscles. Researchers have observed age-related detrimental changes in the NMJ and its ability to regenerate, though at this point it isn't completely clear how these alterations arise from underlying damage. Here is an open access review on this topic:

Autopsy studies in persons who died of acute trauma while relatively healthy have shown that aging is associated with a gradual loss of motor neurons. The mechanism that leads to neuronal loss with aging is still unclear and may involve both impaired trophic signaling from the central nervous system, local degeneration, and feedback from dysfunctional muscle.

Regardless of the cause, when a motor neuron is lost, fibers previously innervated by that neuron, globally defined as a motor unit, are no longer controlled by the nervous system and fail to contribute to the force generated during a volitional muscle contraction. In the attempt to counteract the functional consequence of this process, denervated orphan fibers express proteins and produce chemotactic signals that stimulate the sprouting of new dendrites from residual motor neurons. This process leads re-innervation by the expansion of pre-existing motor units and is aimed at returning to function previously denervated muscle fibers. This dynamic denervation/re-innervation cycle successfully compensates for neuronal loss, with little decline in global strength and only slightly reduced control. However, there is evidence that this compensatory mechanism starts failing with aging. Some denervated fibers are not successfully re-innervated, become apoptotic, and are not replaced by new fibers. It is hypothesized that this phenomenon contributes to a progressive decline in muscle mass and strength with aging.

The reason for a progressive impairment of the re-innervation process with aging is unknown, but some lines of evidence point to changes that occur with aging in the neuromuscular junction (NMJ), which is the synaptic interface between a branch of a motor neuron and muscle cells. Over the last decade, age-associated degeneration of the NMJ has been reported. It has been proposed that such changes may be causally related to the decline in muscle mass and function that occurs in most aging individuals. However, whether changes in the NMJ precede or follow the decline of muscle mass and strength remains unresolved. In this report, we review our current understanding of the events that lead to NMJ dysfunction with aging, including studies on biomarkers, signaling pathways, and animal models. We propose that interventions aimed at preventing the deterioration of the NMJ should be aimed at reversing the mechanisms that lead to NMJ degeneration with aging. It is important to underline that our comprehension of the global mechanism that lead to NJM impairment with aging is still patchy.


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