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Muscle-specific expression of tafazzin or spargel (PGC1-alpha) restores exercise tolerance in a Drosophila model of Barth syndrome

Mitochondrial dysfunction in Barth patients often causes severe exercise intolerance that substantially impacts quality of life. In fact, exercise intolerance is cited as one of the most prominent challenges Barth patients face when trying to live a fulfilling life. These challenges may be further exacerbated by the effects of a sedentary lifestyle. This study seeks to use knowledge gained from exercise training studies in animal models to identify pharmacological and genetic targets that could increase the exercise tolerance of Barth patients.

We developed the first Drosophila endurance training machine, which was used to establish that Drosophila tafazzin (TAZ) mutants have exercise intolerance reminiscent of Barth patients. We report the efficacy of overexpressing various known genetic mimetics of exercise to restore the exercise capacity of TAZ mutants.  Furthermore, we combine these interventions with exercise regimes to assess the potential for endurance training to synergistically enhance the benefits of these therapies.

We first show that expression of wild-type TAZ in muscle alone is enough to rescue exercise capacity of TAZ mutants, indicating that muscle is the key therapeutic target to restore exercise ability. We further show that overexpressing spargel (PGC-1 alpha homolog) specifically in muscle tissue is sufficient to rescue the exercise capacity of TAZ mutants. In addition, we find that the pharmacological agent nicotinamide riboside can restore exercise tolerance in TAZ and that it acts through spargel (PGC-1 alpha homolog) in this context. Together, our results suggests that spargel (PGC-1 alpha homolog) is an important modifier of exercise intolerance in TAZ mutants and should be targeted for future therapies.

Deena Damschroder and Robert Wessells

Department of Physiology, Wayne State University, Detroit, MI

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