Exploration of the Mitochondria as a Potential Therapeutic Target in Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease resulting from a mutation in the X-linked gene encoding the protein dystrophin. DMD is characterized by profound muscle weakness as degenerating muscle is replaced by fat and connective tissue. Early loss of ambulation followed by premature death due to cardiac and/or respiratory failure characterize the most debilitating aspects of DMD, a disease for which there is currently no cure. Limited success has been reported when treating DMD with gene based therapies. Current standard of care involves glucocorticoids, which target a secondary cellular myopathy; inflammation. While this line of treatment has provided promising benefits, these drugs present a variety of negative side effects for patients. As such, extensive research has been focused on identifying both therapeutic targets and corresponding novel therapies for the treatment of the DMD myopathy. The focus of this dissertation was to first determine the degree and precise mechanism of mitochondrial dysfunction in DMD followed by the evaluation of SBT-20, a mitochondrial-targeted peptide, as a therapeutic candidate for the treatment and prevention of DMD pathophysiology. In order to address these questions, we first comprehensively evaluated mitochondrial bioenergetics across a spectrum of oxidative and glycolytic muscles in the D2.B10-DMDmdx/2J mouse (D2.mdx) in early and late stages of disease progression. We then tested the efficacy of SBT-20 in improving both DMD myopathy in respiratory and skeletal muscles, as well as the underlying mechanism of mitochondrial dysfunction in dystrophic muscle.
Our findings reveal that the mitochondrial H2O2 emission is elevated during impaired oxidative phosphorylation in cardiac, respiratory, oxidative and glycolytic muscle in young (4-week) and aged (52-week) D2.mdx mice and furthermore, that there is a specific defect in mtCK functionality in oxidative muscle. SBT-20 was effective in improving mitochondrial bioenergetics following short (4 weeks) and long (12 weeks) term treatment. This was associated with improved pathophysiology following short-term treatment. Taken together, this thesis identifies impairments in mitochondrial bioenergetics as a contributing factor to the pathophysiology in dystrophic muscle and further highlights SBT-20 as a promising therapy for the improvement of myopathy in DMD.