@article {Timpani2022.09.15.508124, author = {Cara A. Timpani and Stephanie Kourakis and Danielle A. Debruin and Dean G. Campelj and Nancy Pompeani and Narges Dargahi and Angelo P. Bautista and Ryan M. Bagaric and Elya J. Ritenis and Lauren Sahakian and Patricia Hafner and Peter G. Arthur and Jessica R. Terrill and Vasso Apostolopoulos and Judy B. de Haan and Nuri Guven and Dirk Fischer and Emma Rybalka}, title = {Dimethyl fumarate modulates the Duchenne muscular dystrophy disease program following short-term treatment in mdx mice}, elocation-id = {2022.09.15.508124}, year = {2022}, doi = {10.1101/2022.09.15.508124}, publisher = {Cold Spring Harbor Laboratory}, abstract = {New medicines are urgently required to treat the fatal neuromuscular disease, Duchenne muscular dystrophy (DMD). DMD involves progressive muscle damage and weakness, which are preceded by oxidative stress, inflammation, and mitochondrial dysfunction. Dimethyl fumarate (DMF) is a potent small molecule nuclear erythroid 2-related factor 2 (Nrf2) activator with current clinical utility in the treatment of multiple sclerosis and psoriasis. Pharmaceutical targeting of Nrf2 by DMF has strong translational potential for DMD, given it: (1) promotes antioxidant defence systems; (2) has a potent immuno-modulatory profile; and (3) can be rapidly re-purposed into clinical care strategies for DMD patients. Here, we tested two weeks of daily 100mg/kg DMF versus 5mg/kg standard care prednisone (PRED) treatment during the peak muscle degeneration period in juvenile mdx mice, the gold standard murine DMD model. Both drugs modulated seed genes driving the DMD disease program and improved muscle force production in fast-twitch muscle. However, only DMF showed pro-mitochondrial effects that protected contracting muscles from fatigue, improved histopathology and augmented clinically compatible muscle function tests. In contrast, PRED treatment stunted mouse growth, worsened histopathology and modulated many normally expressed inflammatory and extracellular matrix (ECM) genes consistent with pan immunosuppression. These findings suggest DMF could be a more selective modulator of the DMD disease program with better efficacy and fewer side effects than standard care PRED therapy warranting follow-up studies to progress clinical translation.Competing Interest StatementER has received consultancy fees from Santhera Pharmaceuticals and Epirium Bio outside the submitted work. NG has received grants and personal consultancy fees from Santhera Pharmaceuticals outside the submitted work. DF is a principal investigator for studies on spinal muscular atrophy sponsored by Hofmann-La Roche LTD. There are no other activities related to commercial companies. The authors declare they have no competing interests.}, URL = {https://www.biorxiv.org/content/early/2022/09/17/2022.09.15.508124}, eprint = {https://www.biorxiv.org/content/early/2022/09/17/2022.09.15.508124.full.pdf}, journal = {bioRxiv} }