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

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. Her...

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Main 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
Format: Article
Language:English
Published: Springer Nature 2022-03-01
Series:EMBO Molecular Medicine
Subjects:
calcium
cardiomyopathy
CD38
DMD
NAD+
Online Access:https://doi.org/10.15252/emmm.202012860
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Summary: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.
ISSN:1757-4676
1757-4684

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