Research Topic

The Redox Regulation of Age-related Denervation-Reinnervation Cycling

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About this Research Topic

The neuromuscular junction (NMJ) defines the functional interface between skeletal muscle and nerve. NMJ loss (i.e. denervation) causes skeletal muscle fiber atrophy and dysfunction. Evidence suggests degenerative cycles of denervation followed by reinnervation contribute to neuromuscular aging: a condition defined by skeletal muscle fiber atrophy and loss. Despite the biological importance of denervation-reinnervation cycling, its biochemical basis remains insufficiently understood. In particular, the functional role of Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) is unclear. For example, whether ROS directly cause or simply reflect the denervated state remains unclear, a situation abetted by the possibility that ROS could divergently regulate denervation-reinnervation cycling (i.e. induce denervation but promote reinnervation). Of course, ROS are chemically heterogeneous, so it is possible that one species may induce denervation while another species induces reinnervation or equally that the same species regulates: with species generators imparting divergent functionality.

Resolving the functional role of ROS and RNS is beset by methodological and technical challenges. For example, measuring ROS poses difficulties owing to their extremely short half-lives (in the order of milliseconds), a situation abetted by difficulties associated with ROS manipulation. Specifically, global ROS manipulation strategies typically fail because they lack the capacity to react with the relevant species in the relevant intracellular compartment at the appropriate time. For example, if mitochondria ROS regulate denervation then manipulation with a redox-active compound that accumulates in the cytosol (e.g. ascorbic acid) will likely fail.

Recently, a number of technical and methodological solutions (i.e. mitochondria targeted redox-active compounds and probes) have been developed that should help better define the functional role of ROS and RNS. Further, the development of conditional Crisper-Cas-9 technology renders conditional redox enzyme genetic manipulations possible. With the capacity to better genetically and chemically manipulate ROS/RNS, it should now be possible to resolve the functional role of ROS/RNS in a neuromuscular aging context.

Here we welcome submissions that address the functional role of ROS/RNS using experimental models of relevance to neuromuscular aging. We also welcome submissions aimed at outlining how new technologies could be exploited to create better NMJ manipulation tools (e.g. development of ROS probes targeted to the NMJ) or genetic strategies to selectively induce denervation. Above all, submissions to this Research Topic should help disambiguate the biological role of ROS/RNS in a neuromuscular aging context.


Keywords: Redox, neuromuscular junction, synaptic plasticity


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

The neuromuscular junction (NMJ) defines the functional interface between skeletal muscle and nerve. NMJ loss (i.e. denervation) causes skeletal muscle fiber atrophy and dysfunction. Evidence suggests degenerative cycles of denervation followed by reinnervation contribute to neuromuscular aging: a condition defined by skeletal muscle fiber atrophy and loss. Despite the biological importance of denervation-reinnervation cycling, its biochemical basis remains insufficiently understood. In particular, the functional role of Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) is unclear. For example, whether ROS directly cause or simply reflect the denervated state remains unclear, a situation abetted by the possibility that ROS could divergently regulate denervation-reinnervation cycling (i.e. induce denervation but promote reinnervation). Of course, ROS are chemically heterogeneous, so it is possible that one species may induce denervation while another species induces reinnervation or equally that the same species regulates: with species generators imparting divergent functionality.

Resolving the functional role of ROS and RNS is beset by methodological and technical challenges. For example, measuring ROS poses difficulties owing to their extremely short half-lives (in the order of milliseconds), a situation abetted by difficulties associated with ROS manipulation. Specifically, global ROS manipulation strategies typically fail because they lack the capacity to react with the relevant species in the relevant intracellular compartment at the appropriate time. For example, if mitochondria ROS regulate denervation then manipulation with a redox-active compound that accumulates in the cytosol (e.g. ascorbic acid) will likely fail.

Recently, a number of technical and methodological solutions (i.e. mitochondria targeted redox-active compounds and probes) have been developed that should help better define the functional role of ROS and RNS. Further, the development of conditional Crisper-Cas-9 technology renders conditional redox enzyme genetic manipulations possible. With the capacity to better genetically and chemically manipulate ROS/RNS, it should now be possible to resolve the functional role of ROS/RNS in a neuromuscular aging context.

Here we welcome submissions that address the functional role of ROS/RNS using experimental models of relevance to neuromuscular aging. We also welcome submissions aimed at outlining how new technologies could be exploited to create better NMJ manipulation tools (e.g. development of ROS probes targeted to the NMJ) or genetic strategies to selectively induce denervation. Above all, submissions to this Research Topic should help disambiguate the biological role of ROS/RNS in a neuromuscular aging context.


Keywords: Redox, neuromuscular junction, synaptic plasticity


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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