Dimethyl fumarate modulates the Duchenne muscular dystrophy disease program following short-term treatment inmdxmice

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.

Loss of endogenous estrogen alters mitochondrial metabolism and muscle clock‐related protein Rbm20 in female mdx mice

“…OCT‐covered gastrocnemius, tibialis anterior (TA) and diaphragm muscles were cryo‐sectioned (10 μm at −15°C) and succinate dehydrogenase (SDH) capacity was quantified as described by us previously 16,35 …”

“…Activity of citrate synthase (CS), an enzyme of the TCA cycle, was measured spectrophotometrically in gastrocnemius homogenates as described by us previously. 16,35 To complement assessment of SDH activity in muscle sections, activity of SDH/mitochondrial ETC complex II (CII) was assessed on isolated mitochondria from gastrocnemius muscles according to the manufacturer directions (Abcam, ab228560). Mitochondria were isolated as performed by us previously.…”

“…11 Mitochondrial and metabolic dysfunction is evident in dystrophic myoblasts 12 and early in the pathological dystrophinopathy milieu leading to muscle degeneration. 13 Targeting mitochondria/metabolism can ameliorate disease pathology in the mdx mouse model of DMD, for example, via mitochondria transplantation 14 or targeted drug therapies (ginovistat targets HDACs, 15 urolithin A activates mitophagy, 11 and dimethyl fumarate targets TCA anaplerosis 16 ).…”

Moderate-term dimethyl fumarate treatment reduces pathology of dystrophic skeletal and cardiac muscle in a mouse model

“…DMF is a potent immunoregulatory and anti-inflammatory and -oxidative drug via nuclear factor erythroid 2-related factor 2 (Nrf2) activation and hydroxycarboxylic acid receptor 2 (HCAR2) agonism (18). Our proof-of-concept study in the mdx mouse demonstrated short-term DMF treatment was more effective against key disease indices than SOC prednisone (PRED), including histopathology, muscle function, mitochondrial metabolism and disease driving gene signatures (19). In the present study, we aimed to evaluate moderate-term effects in mdx mice with an aggravated phenotype.…”

Adenylosuccinic Acid: An Orphan Drug with Untapped Potential

“…Our group is currently investigating the fumarate drug, DMF, for therapeutic application in DMD [ 59 ], and we are interested in comparing the risk–benefit profile of exogenous (via DMF) versus endogenous (via ASA) fumarate-induced Nrf2 targeting. For example, following 2 weeks oral treatment of DMF (100 mg/kg/day) and ASA (325 mg/kg/day), Nrf2 signaling was induced in DMF [ 60 ] but not ASA murine skeletal muscle (C57BL/10 wild-type (WT) and mdx ; unpublished results). Whereas, 8 weeks treatment via the oral route with a comparable dose did induce Nrf2 expression in mdx and WT skeletal muscle [ 14 ].…”