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

Abstract

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.

• Authors: Antoine de Zélicourt, Abdallah Fayssoil, Mbarka Dakouane-Giudicelli, Isley De Jesus, Ahmed Karoui, Faouzi Zarrouki, Florence Lefebvre, Arnaud Mansart, Jean-Marie Launay, Jerome Piquereau, Mariana G Tarragó, Marcel Bonay, Anne Forand, Sophie Moog, France Piétri-Rouxel, Elise Brisebard, Claudia C S Chini, Sonu Kashyap, Matthew J Fogarty, Gary C Sieck, Mathias Mericskay, Eduardo N Chini, Ana Maria Gomez, José-Manuel Cancela, Sabine de la Porte
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 14 Issue 5 Pg. e12860 (05 09 2022) ISSN: 1757-4684 [Electronic] England
• PMID: 35298089 (Publication Type: Journal Article)
• Copyright: © 2022 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• NAD
• NAD+ Nucleosidase
• ADP-ribosyl Cyclase 1

Topics

• ADP-ribosyl Cyclase 1
• Animals
• Humans
• Mice
• Mice, Inbred mdx
• Muscle, Skeletal
• Muscular Dystrophy, Duchenne (genetics)
• Myocytes, Cardiac (pathology)
• NAD (genetics, therapeutic use)
• NAD+ Nucleosidase (genetics)
• Phenotype