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 receptor 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⁺ signaling, led to a fully restored heart function and structure, with skeletal muscle performance improvements, associated with a reduction in inflammation and senescence markers. Muscle NAD⁺ levels were also fully restored, while the levels of the two main products of CD38, nicotinamide and ADP-ribose, 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 isatuximab (SARCLISA^®) 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.