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.
Highlights
Duchenne’s muscular dystrophy (DMD) is a progressive, fatal muscle wasting disorder caused by mutations within the dystrophin gene that affects 1:5000–10000 boys[1]
Mice receiving SR8278 showed no elevation in the hepatic toxicity markers alanine aminotransferase (ALT), alkaline phosphatase (ALP) and urea suggesting that SR8278 was well tolerated and had no hepatotoxic effects (Supplementary Fig. 1A)
We found that SR8278 effectively stabilized lean mass, improved skeletal muscle (SkM) function, reduced fibrosis and stimulated SkM repair and mitochondrial biogenesis in dystrophic muscle
Summary
Duchenne’s muscular dystrophy (DMD) is a progressive, fatal muscle wasting disorder caused by mutations within the dystrophin gene that affects 1:5000–10000 boys[1]. DMD is treated clinically with glucocorticoids, which slow loss of motor function and muscle turnover, possibly by inhibiting fibrosis[6,7]. Inuitively appealing methods; exon skipping therapies, that attempt to rescue dystrophin protein expression in skeletal muscle (SkM) have been tested in patients[12,13,14]. These treatments utilize antisense oligonucleotides (AONs) to modify mRNA splicing of dystrophin transcripts and can potentially yield therapeutic benefits in about 83% of DMD patients. The small molecule drug ataluren, which promotes ribosomal skipping of premature stop codons has been successfully used to rescue functional dystrophin expression and muscle function in DMD. We have shown that targeted disruption of REV-ERB activity stimulated muscle regeneration in response to acute injury[26], suggesting that REV-ERB antagonists may be therapeutically beneficial in an assortment of myopathies
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