CD38: New target in Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a genetic disease due to the lack of dystrophin, a subsarcolemmal protein, which leads to muscle plasmatic membrane fragility. The patients suffer from a progressive weakness and degeneration (necrosis) accompanied by inflammation of skeletal and cardiac muscles. The main cause of patient death, in DMD adults, is due to pathological cardiac phenotype, leading to severe dilated cadiomyopathy and heart failure. One key mechanism leading to muscle cells degeneration is linked to high cytosolic Ca2+ concentration observed in the DMD muscle cells, including cardiomyocytes. In this sense, several studies have shown that ryanodine receptors (RyRs), the Ca release channels of the sarcoplasmic reticulum are leaky in the mdx mouse, the main DMD rodent model, and generating the abnormal RyRs spontaneous Ca2+ activity in DMD. We propose to target this Ca2+ homeostasis deregulation, and particularly the RyRs leak, by inhibiting CD38, an enzyme which produces two Ca2+ releasing messengers: cADPR and NAADP. cADPR activates RyRs and NAADP recruits the endolysosomal calcium store, and it has also been proposed to enhance the RyRs sensitivity through Ca2+-induced Ca2+ release. In order to test this hypothesis, we evaluated the cardiac benefic effects of CD38 deletion by generating an mdx/CD38−/− mouse. We measured the RyRs spontaneous Ca2+ activity and sensitivity with Ca2+ imaging (confocal fluorescence microscopy) in isolated cardiomyocytes, the heart necrosis with Masson's trichrome staining, and the cardiac function by echocardiography. We show that CD38 deletion in the mdx completely normalized the pathological spontaneous Ca2+ activity in cardiomyocytes, reduced the heart necrosis and normalized the left ventricle dilatation and the left ventricular ejection fraction, both impaired in the mdx mouse. We propose here an innovative strategy by targeting a Ca2+ homeostasis modulator, CD38, what could lead to new therapeutic perspectives.