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Investigational Therapy SR8278 Shown to Regenerate Muscle in DMD Mice Study

Scientists at Saint Louis University believe that an investigational therapy called SR8278 holds potential for treating Duchenne muscular dystrophy (DMD) after it was shown to increase muscle function and decrease muscle fibrosis in lab mice.

The discovery follows the team’s research of the nuclear receptor REV-ERB, which regulates key processes in the body, including muscle generation, according to a news release.

The results were highlighted in the study, “Pharmacological inhibition of REV-ERB stimulates differentiation, inhibits turnover and reduces fibrosis in dystrophic muscle,” published in Nature Scientific Reports.

DMD is characterized by the absence of the protein dystrophin, which leads to excessive damage in normal tissue and results in ongoing cycles of muscle destruction and regeneration. While a number of treatments currently under investigation show promise, they only work to delay progression. Pharmacological therapies that are safe and fight muscle wasting and fibrosis are still needed.

The nuclear receptor REV-ERB works to either activate or suppress the activity of certain genes. It has been shown that disruption of REV-ERB signaling leads to stimulation of muscle regeneration in response to injury, suggesting that therapies that are antagonistic to REV-ERB may be beneficial.

The researchers at Saint Louis University School of Medicine set out to determine whether disruption of REV-ERB activity using the REV-ERB antagonist SR8278 would be beneficial in a mouse model of DMD. First, they showed that treatment with SR8278 led to an increase in lean muscle mass and improvement of muscle function, as tested by grip strength assessment, in mouse models of DMD. Researchers also showed that SR8278 stabilized skeletal muscle in these mice without any overt toxicity.

Next, they showed that SR8278 improved muscle architecture and decreased fibrosis in the DMD mice. They also found that antagonizing REV-ERB led to an increase in factors involved in myogenesis — the formation of muscle tissue — which leads to stabilization of lean muscle mass. Researchers also showed that treatment with SR8278 led to an increase in the production of mitochondria, the powerhouse of cells.

The Wnt signaling pathway controls development and plays a major role in muscle repair and the self-renewal of cells. Researchers showed that antagonizing REV-ERB regulates Wnt signaling, which could be a mechanism through which SR8278 promotes muscle regeneration and improves muscle function.

Results from the study suggest that REV-ERB antagonism led to an improvement in muscle function, decreased fibrosis, and stimulated mitochondrial production, possibly through regulation of the Wnt signaling pathway.

“These results suggest that REV-ERB is a potent target for the treatment of DMD,” Thomas Burris, PhD, chair of pharmacology and physiology at Saint Louis University, said in a press release. “This is an encouraging finding as we search for better treatments for those with this debilitating illness.”

 

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