The CD38-NADase is a new major contributor to Duchenne muscular dystrophic phenotype

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration. Two important deleterious features are a Ca2+ dysregulation linked to Ca2+ influxes associated with ryanodine receptors hyperactivation, and a muscular nicotinamide adenine dinucleotide (NAD+) deficit. Here, we identified that deletion in mdx mice of CD38, a NAD+ glycohydrolase producing modulators of Ca2+ signalling, led to a fully restored heart function and structure, with skeletal muscle performance improvements, associated with a reduction of inflammation and senescence markers. Muscle NAD+ levels were also fully restored while the levels of the two main products of CD38, nicotinamide and APDribose were reduced, in heart, diaphragm, and limb. In cardiomyocytes from mdx/CD38-/- mice, the pathological spontaneous Ca2+ activity was reduced, as well as in myotubes from DMD patients treated with a monoclonal anti-CD38 antibody. Finally, treatment of mdx and utrophin-dystrophin deficient (mdx/utr-/-) mice with CD38 inhibitors resulted in improved skeletal muscle performances. Thus, we demonstrate that CD38 actively contributes to DMD physiopathology. We propose that a selective anti-CD38 therapeutic intervention could be highly relevant to develop for DMD patients.