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Review
. 2021 May 24;10(6):1307.
doi: 10.3390/cells10061307.

Age-Related Alterations at Neuromuscular Junction: Role of Oxidative Stress and Epigenetic Modifications

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Review

Age-Related Alterations at Neuromuscular Junction: Role of Oxidative Stress and Epigenetic Modifications

Gabriella Dobrowolny et al. Cells. .

Abstract

With advancing aging, a decline in physical abilities occurs, leading to reduced mobility and loss of independence. Although many factors contribute to the physio-pathological effects of aging, an important event seems to be related to the compromised integrity of the neuromuscular system, which connects the brain and skeletal muscles via motoneurons and the neuromuscular junctions (NMJs). NMJs undergo severe functional, morphological, and molecular alterations during aging and ultimately degenerate. The effect of this decline is an inexorable decrease in skeletal muscle mass and strength, a condition generally known as sarcopenia. Moreover, several studies have highlighted how the age-related alteration of reactive oxygen species (ROS) homeostasis can contribute to changes in the neuromuscular junction morphology and stability, leading to the reduction in fiber number and innervation. Increasing evidence supports the involvement of epigenetic modifications in age-dependent alterations of the NMJ. In particular, DNA methylation, histone modifications, and miRNA-dependent gene expression represent the major epigenetic mechanisms that play a crucial role in NMJ remodeling. It is established that environmental and lifestyle factors, such as physical exercise and nutrition that are susceptible to change during aging, can modulate epigenetic phenomena and attenuate the age-related NMJs changes. This review aims to highlight the recent epigenetic findings related to the NMJ dysregulation during aging and the role of physical activity and nutrition as possible interventions to attenuate or delay the age-related decline in the neuromuscular system.

Keywords: ALS; ROS; aging; exercise; nutrition; oxidative stress; skeletal muscle.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of NMJ architecture. NMJ is composed of three major elements: the presynaptic motor nerve terminals packed with synaptic vesicles containing the neurotransmitter ACh; the synaptic cleft; and the deeply folded postsynaptic membrane of the muscle fiber, where AChRs are placed. The NMJ-associated cells, tSCs, and kranocytes are also shown.
Figure 2
Figure 2
Oxidative stress and NMJ instability. Excessive ROS production during aging or neurodegenerative disorder is responsible for the increased denervation and skeletal muscle atrophy, cellular protein oxidation, mitochondrial dysfunction, and impairment of autophagic flux, leading to NMJ instability.
Figure 3
Figure 3
Nutrient-dependent epigenetic modifications involved in NMJ remodeling during aging. Nutrients and diet compounds may affect histone modifications and miRNAs expression, counteracting NMJ dismantlement involved in the onset of sarcopenia.

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