MR Assessment of the effect of nNOS on Bioenergetics and Microvascular Function in Becker and Duchenne Muscular Dystrophy - Project Summary The overall objective of this project is to evaluate the potential of magnetic resonance (MR) measures of bioenergetics and microvascular function to track disease progression and treatment in dystrophic muscle. Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness, fatigue, deteriorating functional capabilities, loss of independence, and early death. Muscles in individuals with DMD are deficient in dystrophin, which is accompanied by a lack of sarcolemma-localized neuronal nitric oxide synthase mu (nNOSμ). Gene therapies aimed at delivering micro-dystrophin genes are emerging as viable therapeutic options in DMD; however, a number of questions remain. Currently, the significance of the nNOSμ domain of micro-dystrophin is not clear. It has been proposed that nNOSμ plays an important role in preventing fatigue and maintaining blood flow during and following activity. We have previously shown that muscle energetic status is altered, mitochondria function compromised, and microvascular responses are impaired in DMD compared to unaffected controls using 31phosphorus-magnetic resonance spectroscopy (31P-MRS) and magnetic resonance imaging (MRI). In this project, we propose to evaluate the effects of current and emerging approaches of gene delivery of micro-dystrophin with and without the nNOSμ domain when combined with exercise in dystrophic mouse models using ultrahigh field MR (Aim 1). Furthermore, we will determine the responsiveness of energetic and microvascular function measures to disease progression directly in individuals with DMD by performing a natural history longitudinal study over three years; this aim will also include a subgroup who are treated with Elevidys, a recently FDA-approved gene therapy for DMD (Aim 2). In addition, to evaluate the role of nNOSμ on muscle energetic status, in vivo oxidative capacity, and microvascular function, we will compare participants with Becker muscular dystrophy (BMD) who have dystrophin mutations with or without the nNOSμ domain (Aim 3). Collectively, we hypothesize that MR measures of bioenergetics and microvascular function will be responsive to disease progression and will be effective in monitoring improvements with treatments targeting restoring dystrophin with sarcolemma localized nNOSμ in dystrophic muscle. We anticipate that our findings will lead to the validation of noninvasive quantitative techniques that can be implemented to evaluate potential interventions targeted at improving mitochondria and vascular function in muscular dystrophies and other neuromuscular diseases.
