Dimethyl fumarate modulates the dystrophic disease program following short-term treatment
Cara A. Timpani, Stephanie Kourakis, Danielle A. Debruin, Dean G. Campelj, Nancy Pompeani, Narges Dargahi, Angelo P. Bautista, Ryan M. Bagaric, Elya J. Ritenis, Lauren Sahakian, Didier Debrincat, Nicole Stupka, Patricia Hafner, Peter G. Arthur, Jessica R. Terrill, Vasso Apostolopoulos, Judy B. de Haan, Nuri Guven, Dirk Fischer, Emma Rybalka
Cara A. Timpani, Stephanie Kourakis, Danielle A. Debruin, Dean G. Campelj, Nancy Pompeani, Narges Dargahi, Angelo P. Bautista, Ryan M. Bagaric, Elya J. Ritenis, Lauren Sahakian, Didier Debrincat, Nicole Stupka, Patricia Hafner, Peter G. Arthur, Jessica R. Terrill, Vasso Apostolopoulos, Judy B. de Haan, Nuri Guven, Dirk Fischer, Emma Rybalka
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Research Article Muscle biology Therapeutics

Dimethyl fumarate modulates the dystrophic disease program following short-term treatment

Abstract

New medicines are urgently required to treat the fatal neuromuscular disease Duchenne muscular dystrophy (DMD). Dimethyl fumarate (DMF) is a potent immunomodulatory small molecule nuclear erythroid 2-related factor 2 activator with current clinical utility in the treatment of multiple sclerosis and psoriasis that could be effective for DMD and rapidly translatable. Here, we tested 2 weeks of daily 100 mg/kg DMF versus 5 mg/kg standard-care prednisone (PRED) treatment in juvenile mdx mice with early symptomatic DMD. Both drugs modulated seed genes driving the DMD disease program and improved force production in fast-twitch muscle. However, only DMF showed pro-mitochondrial effects, protected contracting muscles from fatigue, improved histopathology, and augmented clinically compatible muscle function tests. DMF may be a more selective modulator of the DMD disease program than PRED, warranting follow-up longitudinal studies to evaluate disease-modifying impact.

Authors

Cara A. Timpani, Stephanie Kourakis, Danielle A. Debruin, Dean G. Campelj, Nancy Pompeani, Narges Dargahi, Angelo P. Bautista, Ryan M. Bagaric, Elya J. Ritenis, Lauren Sahakian, Didier Debrincat, Nicole Stupka, Patricia Hafner, Peter G. Arthur, Jessica R. Terrill, Vasso Apostolopoulos, Judy B. de Haan, Nuri Guven, Dirk Fischer, Emma Rybalka

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Figure 5

DMF enhances mitochondrial respiratory function in mdx FDB fibers.

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DMF enhances mitochondrial respiratory function in mdx FDB fibers. (A) O...
(A) Oxygen consumption rate was measured using Seahorse extracellular flux and chemical inhibitors and uncouplers of mitochondrial respiration. (B) Basal, (C) ATP-linked, (D) maximal, and (E) nonmitochondrial respiration in mdx fibers. (F) Metabolic phenotypes in response to chemical uncoupling, (G) coupling efficiency, (H) SRC, and (I) citrate synthase (CS) activity are also shown. (J) Succinate dehydrogenase (SDH) capacity was used to estimate fiber type shifts (K–O) and (P–T) representative images are shown. Data presented in A–J are mean ± SEM and n are indicated by individual data points unless otherwise stated. Data presented in K–O are mean percentage fiber SDH density across 3 bins. Panel A and F n: WT VEH = 13, WT DMF = 7, mdx VEH = 9, mdx DMF = 7, mdx PRED = 7. Panel K–O n: WT VEH = 9, WT DMF = 4, mdx VEH = 4, mdx DMF = 5, mdx PRED = 6. Statistical significance in B–J was tested by 2-way (genotype and DMF treatment) and 1-way (mdx treatment) ANOVA. Treatment effect: *P < 0.05, **P < 0.01, ****P < 0.0001; genotype effect: ###P < 0.001. (P–T) Scale bar = 50 mm.