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Slowing the progression of muscular dystrophy
Published in the Nature journal Scientific Reports, Saint Louis University (SLU) researchers report a new drug reduces fibrosis (scarring) and prevents loss of muscle function in an animal model of Duchenne muscular dystrophy (DMD).
DMD is a fatal form of a muscle wasting disorder affecting one in every 5,000 to 10,000 boys. It is caused by mutations on the X chromosome in the gene encoding dystrophin protein found in muscle fibers. Dystrophin is a structural protein that protects the sarcolemma membrane surrounding muscles from stresses produced in muscle contractions. However, over the last 10 years more and more evidence reveals the loss of dystrophin causes dysfunction in multiple muscle pathways, all contributing to DMD.
DMD patients go through continuous cycles of muscle destruction and regeneration which promotes inflammed muscle tissue, scarring and eventual loss of function. With treatment, men with DMD live on average about 25 years, needing a wheelchair by age 12, and mechanical ventilation to help their breathing.
Working together, Thomas Burris and Colin Flaveny are hoping to develop synthetic compounds that stimulate nuclear receptors in muscle cells to rescue the affects of DMD. Nuclear hormone receptors are proteins that bind to another target protein to act as on-off switches controlling its function. In their joint research, Burris and Flaveny found a nuclear receptor known to regulate cholesterol.
Cholesterol is one of the most important substances in our body as it helps stabilize the cell membrane. Two types of lipoproteins carry cholesterol to and from cells. One is low-density lipoprotein, or LDL. Colin Flaveny PhD, an assistant professor of pharmacology and physiology at Saint Louis University (SLU), previously studied the nuclear receptor REV-ERB as it regulates our internal clock. Burris as chair of pharmacology and physiology at SLU, works on how a body's natural hormones operate and earlier this year, published new findings showing that REV-ERB is involved in lowering LDL cholesterol.
"Recently, we found that REV-ERB appears to play a unique role in every stage of muscle tissue development."
Together, Flaveny and Burris identified that a decrease in funcion of REV-ERB leads myoblast or muscle cells to differentiate. Conversely, an increase in REV-ERB function affects the metabolic function of skeletal muscle. Knowing that a drug called SR8278 inhibits REV-ERB, Burris and Flaveny explored whether SR8278 could slow the progression of muscular dystrophy in a mouse modelling the disorder. They observed in mice that SR8278 increased lean muscle mass and function while decreasing muscle scarring and protein loss.
"These results suggest that REV-ERB is a potent target for treatment of DMD. This is an encouraging finding as we search for better treatments for this debilitating illness."
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.
Authors: Ryan D. Welch, Cyrielle Billon, Aurore-Cecile Valfort, Thomas P. Burris & Colin A. Flaveny.
Other researchers on the project include Ryan D. Welch, Cyrielle Billon and Aurore-Cecile Valfort.
After 48 hours of differentiating, cells where exposed to 5uM of SR8278 in a DMSO vehicle with or without the presence of LiCl (10 mM, Sigma Aldrich) or WntC59 (100uM, Bio-Techne) for 48 hours. The media with ligand and/or wnt modulators where replenished every 24 hours. The C2C12 cells were then lysed and their RNA isolated for future qPCR analysis.
The study was supported by a grant from the National Institutes of Health (grant number MH093429).
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Muscular Dystrophy discussion with kids.
Image credit: Watch video of this discussion filmed by Cut.com