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 3

DMF activates Nrf2 and induces the phase II antioxidant response in mdx skeletal muscle.

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DMF activates Nrf2 and induces the phase II antioxidant response in mdx ...
Protein expression of (A) Nrf2, (B) NAD(P)H dehydrogenase:quinone oxidoreductase (NQO1), (C) superoxide dismutase 1 (SOD1), (D) hemeoxygenase-1 (HO-1), (I) kelch-like ECH-associated protein 1 (Keap1), and (F) sequestosome 1 (p62) was quantitated via Western blot. (G and H) The muscle inflammatory response was assessed by quantitative real-time polymerase chain reaction (qRT-PCR) gene array. (I) Phosphorylated nuclear factor-κB (NF-κB) and total NF-κB protein and (J–O) CD68-positive (CD68+) macrophages. (P) Gene signatures of M1 and M2 macrophages were extrapolated from gene array data presented in H. Data in G, H, and K are based on log2 fold-change from WT (for mdx VEH) and mdx VEH (for mdx DMF and PRED) derived from n = 4/group where each n is pooled mRNA for n = 2 mice. Statistical significance was tested by 1-way ANOVA. H heatmap was partially published previously under CC BY license (73). Data presented in A–F, I, and J are mean ± SEM, and n are indicated by individual data points. Statistical significance was tested by 2-way (genotype and DMF treatment) and 1-way (mdx treatment) ANOVA. Treatment effect: *P < 0.05, ****P < 0.0001; genotype effect: #P < 0.05, ####P < 0.0001. (K–O) Scale bar = 20 mm.