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

Duchenne muscular dystrophy (DMD) is a fatal muscle wasting condition resulting from the loss of the structural protein dystrophin. The disease is characterized by severe muscle wasting and weakness that results in early death due to cardiac and/or respiratory failure. Currently, there is no cure for DMD and current standard of care (glucocorticoid steroids) only addresses secondary pathologies, and is accompanied with a myriad of negative side effects. Previous work has established the mitochondria as a contributor to dystrophic pathology and a valid therapeutic target.

The primary focus of this thesis was to examine novel therapies that modulate metabolism in DMD, to determine if secondary pathologies, including fibrosis, atrophy, weakness and mitochondrial stress are attenuated. Additionally, we aimed consider the effects of adenylates and creatine metabolism on mitochondrial permeability transition (mtPT) in a permeabilized muscle fibre system. Our study findings reveal that ATP significantly attenuates mtPT and that both creatine and ADP should be considered in buffer composition for assessment of mtPT.

Next, using the mitochondrial-enhancing compound, Olesoxime, we examined the effect of attenuating mitochondrial stress on dystrophic pathology. Unexpectedly, improvements to mitochondrial respiration and reactive oxygen species attenuation, were creatine-dependent, indicating that creatine sensitivity was preserved by Olesoxime treatment. These improvements to bioenergetics also happened in association with markers of muscle breakdown (serum creatine kinase), and improvement in muscle function (cage hand time and recovery of diaphragm force after fatigue). Finally, short-term treatment with the novel adiponectin receptor agonist, ALY688-SR, mitigated aspects of mitochondrial stress in quadriceps, diaphragm and hippocampus, while improving markers of fibrosis and muscle atrophy in the diaphragm, and recognition memory.

Overall, this thesis indicates that attenuating mitochondrial stress in dystrophic muscle and brain improves markers of muscle function and quality, while preserving cognitive function and warrants longer term treatment protocols.