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

• Published in: EMBO molecular medicine Vol. 14; no. 5; pp. e12860 - n/a
• Main Authors: de Zélicourt, Antoine, Fayssoil, Abdallah, Dakouane‐Giudicelli, Mbarka, De Jesus, Isley, Karoui, Ahmed, Zarrouki, Faouzi, Lefebvre, Florence, Mansart, Arnaud, Launay, Jean‐Marie, Piquereau, Jerome, Tarragó, Mariana G, Bonay, Marcel, Forand, Anne, Moog, Sophie, Piétri‐Rouxel, France, Brisebard, Elise, Chini, Claudia C S, Kashyap, Sonu, Fogarty, Matthew J, Sieck, Gary C, Mericskay, Mathias, Chini, Eduardo N, Gomez, Ana Maria, Cancela, José‐Manuel, de la Porte, Sabine
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.05.2022; EMBO Press; Wiley Open Access; John Wiley and Sons Inc; Springer Nature
• Subjects: ADP-ribosyl Cyclase 1; Animals; Apoptosis; calcium; Calcium signalling; Cardiomyocytes; Cardiomyopathy; CD38; CD38 antigen; Degeneration; Diaphragm; Disease; DMD; Duchenne's muscular dystrophy; Dystrophin; EMBO25; Enzymes; Heart failure; Homeostasis; Humans; Investigations; Life Sciences; Mice; Mice, Inbred mdx; Monoclonal antibodies; Muscle, Skeletal; Muscular dystrophy; Muscular Dystrophy, Duchenne - genetics; Myocytes, Cardiac - pathology; Myotubes; NAD; NAD - genetics; NAD - therapeutic use; NAD+ Nucleosidase - genetics; Pathogenesis; Patients; Phenotype; Phenotypes; Plasma; Proteins; Ribose; Senescence; Skeletal muscle; Structure-function relationships; Utrophin; NAD; CD38; DMD; calcium; cardiomyopathy
• ISSN: 1757-4676; 1757-4684; 1757-4684
• DOI: 10.15252/emmm.202012860

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration. Two important deleterious features are a Ca 2+ dysregulation linked to Ca 2+ 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 Ca 2+ 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 Ca 2+ 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. Synopsis Duchenne muscular dystrophy (DMD) is characterized by muscle NAD + deficit and muscle Ca 2+ overload. In various dystrophic mouse models and a human DMD cell culture, we have targeted the multifunctional enzyme CD38, a NAD + glycohydrolase which generates Ca 2+ signaling modulators from NAD + , by genetic or pharmacological inhibition. We show: A fully restored cardiac function. Fully restored NAD + levels concomitantly with normalized Ca 2+ signalling. Improved skeletal muscle performances in the severely affected dystrophin/utrophin‐deficient mice. Reduced Ca 2+ leak displayed by patients DMD myotubes treated with SARCLISA ® , a monoclonal anti‐CD38 antibody, suggesting a novel therapeutic strategy. Graphical Abstract Duchenne muscular dystrophy (DMD) is characterized by muscle NAD + deficit and muscle Ca 2+ overload. In various dystrophic mouse models and a human DMD cell culture, we have targeted the multifunctional enzyme CD38, a NAD + glycohydrolase that generates Ca 2+ signaling modulators from NAD + , by genetic or pharmacological inhibition.