Figure 2.

Proposed approach for nitric oxide (NO) therapy in Duchenne Muscular Dystrophy (DMD). (A) Dystrophic muscle is characterized by mitochondria which produce elevated reactive oxygen species (ROS) and reduced adenosine triphosphate (ATP). Along with other pathological processes, this culminates in muscle damage and wasting which impairs function. (B) We have previously demonstrated that the use of chronic nitrate supplementation to increase the NO pool is detrimental in dystrophic murine muscle. The superfluous ROS reacts with the NO to produce peroxynitrite (ONOO^–) which amplifies muscle damage. As such, manipulation of the nitrate-nitrite-NO pathway and NO donor/signal amplifier drugs are unfeasible as a treatment for DMD as they currently stand. (C) Since we observed that the increased muscle damage in dystrophic murine muscle was accompanied by markers of higher regenerative capacity (i.e., centronucleated muscle fibers), we postulate that a combination therapy/dual function small molecule which increases NO bioavailability while addressing the oxidative stress may be beneficial rather than damaging. (D) Alternatively, increasing endogenous NO signaling e.g., through endothelial NOS (eNOS) with compounds such as resveratrol could circumvent the loss of nNOS-mediated NO signaling and restore physiologically relevant NO levels to induce benefits such as enhanced capillarization and muscle oxygenation. Image created with BioRender.com.