Pharmacological inhibition of REV-ERB stimulates differentiation, inhibits turnover and reduces fibrosis in dystrophic muscle

Abstract

Duchenne muscular dystrophy (DMD) is a debilitating X-linked disorder that is fatal. DMD patients lack the expression of the structural protein dystrophin caused by mutations within the DMD gene. The absence of functional dystrophin protein results in excessive damage from normal muscle use due to the compromised structural integrity of the dystrophin associated glycoprotein complex. As a result, DMD patients exhibit ongoing cycles of muscle destruction and regeneration that promote inflammation, fibrosis, mitochondrial dysfunction, satellite cell (SC) exhaustion and loss of skeletal and cardiac muscle function. The nuclear receptor REV-ERB suppresses myoblast differentiation and recently we have demonstrated that the REV-ERB antagonist, SR8278, stimulates muscle regeneration after acute injury. Therefore, we decided to explore whether the REV-ERB antagonist SR8278 could slow the progression of muscular dystrophy. In mdx mice SR8278 increased lean mass and muscle function, and decreased muscle fibrosis and muscle protein degradation. Interestingly, we also found that SR8278 increased the SC pool through stimulation of Notch and Wnt signaling. These results suggest that REV-ERB is a potent target for the treatment of DMD.

Rev-erbα heterozygosity produces a dose-dependent phenotypic advantage in mice

“…The data indicates that partial loss of Nr1d1 gene does not produce deleterious effects and effectively augments metabolic substrate preference. This aligns well with our previous studies in which we showed that REV-ERB inhibition is an effective approach for pharmacologically stimulating muscle repair [16,17].…”

“…Previously, we have highlighted that REV-ERB directs myogenesis through tethered interaction with the transcription complex Nuclear Factor-Y [16]. Moreover, inhibiting REV-ERB with a synthetic antagonist enhanced muscle repair in an acute injury model and slowed disease progression in a model of Duchenne's muscular dystrophy [16,17]. Loss of Rev-Erb in contrast to Rev-Erb was also shown to stimulate skeletal muscle metabolism and fatty acid oxidation [18].…”

Transcriptional programming of lipid and amino acid metabolism by the skeletal muscle circadian clock

“…Our data thus support the idea that specifically inhibiting muscle REV-ERBα/β [ 124 ] in certain situations may provide a relatively safe means to temporarily modulate metabolic efficiency and EE in skeletal muscle, a major oxidative tissue and relevant pharmacological target in humans [ 125 , 126 ]. Indeed, pioneering groups have already begun to wade into these therapeutic waters and, importantly, have already shown in mice that selective REV-ERB antagonism accelerates muscle regeneration in response to acute muscle injury [ 99 ] and promotes muscle differentiation and maintenance of muscle mass in a model of Duchenne muscular dystrophy (DMD) [ 127 ]. Intriguingly, Welch and colleagues showed REV-ERB antagonism enhances Wnt and Notch signaling, leading to satellite cell self-renewal.…”

The circadian clock protects against ionizing radiation‐induced cardiotoxicity

“…To further understand the Bmal1‐related mechanism on a cellular level, we used synchronized rat cardiomyocytes (H9c2), a cell line derived from rat heart. Cardiomyocytes have been shown to exhibit robust circadian rhythms, and recent studies showed that antagonism of the Bmal1 repressor protein, Rev‐erbα, offered cardioprotection to cardiac surgery patients from perioperative myocardial ischaemia‐reperfusion injury and reduced fibrosis in dystrophic muscle . Hence, we reasoned that decrease in Bmal1 via increased Rev‐erbα will be deleterious in cardiomyocytes.…”

“…Cardiomyocytes have been shown to exhibit robust circadian rhythms, 15 and recent studies showed that antagonism of the Bmal1 repressor protein, Rev-erbα, offered cardioprotection to cardiac surgery patients from perioperative myocardial ischaemia-reperfusion injury and reduced fibrosis in dystrophic muscle. [43][44][45] Hence, we reasoned that decrease in Bmal1 via increased Rev-erbα will be deleterious in cardiomyocytes. To test this, we treated H9c2 cells with 25 µM of the Rev-erbα agonist, SR9011, to inhibit Bmal1 compared to DMSO controls, with maximum effect seen at 48 hours ( Figure S4D).…”