Promising therapeutic approach for Duchenne muscular dystrophy-sarcolipin reduction
Introduction: Duchenne muscular dystrophy (DMD), owing to the gene mutation of dystrophin, is a severe genetic disease resulting in body-wide muscle degeneration and necrosis in boys and young men. Lots of evidence demonstrates that an important early pathogenic event from DMD patients is the abnormal elevation of intracellular Ca2+, resulting from the dysfunction of SERCA, which is in charge of more than 70% of Ca2+ removal from the cytosol. Therefore, strategies to up-regulate the expression of SERCA or stabilize the SERCA activity may be good therapies to ameliorate muscle pathology of DMD patients.
Today, sarcolipin (SLN)，an inhibitor of SERCA has been discovered by one research team at Rutgers New Jersey Medical School. Down-regulation of SLN results in restore of SERCA function and muscle function improvement, which might be a promising therapeutic approach for DMD in the future.
This result entitled by “Reducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice” was published online on Oct 20th in the journal of Nature Communications. In the study, the authors found that sarcolipin (SLN), an inhibitor of SERCA, is abnormally upregulated in the dystrophin mutant (mdx) and dystrophin /utrophin double mutant mouse models of DMD. However, whether SLN upregulation underlies SERCA dysfunction and conduces to the muscle pathogenesis in DMD still needs to be clarified.
To identify the physiological relevance of SLN upregulation with SERCA dysfunction, the scientists knocked down SLN with AAV9-mediated RNA interference approach, showing that loss function of SLN by AAV9 restores SERCA function in DMD mouse models. Meanwhile, muscle pathology is obviously ameliorated, the diaphragm, skeletal muscle and cardiac function are greatly improved.
As such, this study discovered an effective means, i.e. SLN reduction, to mitigate Duchenne muscular dystrophy, which not only improves the SERCA function but also ameliorates the features of muscular dystrophy and cardiomyopathy, providing a promising therapeutic approach for DMD.
1. Duchenne muscular dystrophy.
2. Review of Duchenne muscular dystrophy (DMD) for the pediatricians in the community.
3. Reducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice.
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