MR Assessment of Bioenergetics and Microvascular Function in Dystrophic Muscle

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Project Summary The overall objective of this project is to evaluate the potential of novel magnetic resonance imaging (MRI) and localized 31phosphorus-magnetic resonance spectroscopy (31P-MRS) measures of bioenergetics and microvascular function to monitor disease progression and treatment in dystrophic muscle. Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness, deteriorating functional capabilities, loss of independence, and early death. Muscles in children with DMD are deficient in dystrophin, which is accompanied by a lack of sarcolemma-localized neuronal nitric oxide synthase (nNOS). Although there is no cure for DMD, a number of promising therapies are being developed and evaluated, and young boys are predominantly being targeted as subjects. However, reliable markers of disease progression are lacking, particularly in young boys. Recent studies have shown considerable promise in muscle energetic status measured with 31P-MRS as an early marker of pathology in dystrophic muscle. The cause of these energetic disturbances (e.g., reduced phosphocreatine) is poorly understood, as well as the response to disease progression and treatment. The lack of neuronal nitric oxide synthase (nNOS) in dystrophic muscle has been attributed to cause reduced blood flow during and following skeletal muscle contractions in DMD, and may also contribute to the reported energetic perturbations and increased susceptibility to damage in dystrophic muscle. In aim 1 we will use a murine model (mdx) to provide insight into the relationship between energetic status and microvascular function in dystrophy using high resolution MR. In aim 2, we will establish the effects of treatment with an established AAV-microdystrophin vector with and without the nNOS binding domain. Finally, in aim 3, we will apply these methods to the lower extremity of boys with DMD and unaffected controls in a range of ages using a cross sectional design. MR measures will evaluate 1) heterogeneity of energetic status among muscles using 31P 2D chemical shift imaging and 2) microvascular function using MRI blood oxygenation-level dependent (BOLD) contrast and arterial spin labeling (ASL). Furthermore, we will test the day-to-day variability of these measures in DMD and controls. The overall hypothesis of this project is that localized MR measures of bioenergetics and microvascular function will enable early detection of disease pathology at a young age, will be responsive to disease progression, and will be effective in monitoring improvements with treatment in dystrophic muscle. We anticipate that the results will lead to reproducible methods that can be implemented to evaluate potential treatments targeted at DMD and other neuromuscular diseases.