Open AccessCD38‐NADase is a new major contributor to Duchenne muscular dystrophic phenotype
Author(s) -
Zélicourt Antoine,
Fayssoil Abdallah,
DakouaneGiudicelli Mbarka,
De Jesus Isley,
Karoui Ahmed,
Zarrouki Faouzi,
Lefebvre Florence,
Mansart Arnaud,
Launay JeanMarie,
Piquereau Jerome,
Tarragó Mariana G,
Bonay Marcel,
Forand Anne,
Moog Sophie,
PiétriRouxel France,
Brisebard Elise,
Chini Claudia C S,
Kashyap Sonu,
Fogarty Matthew J,
Sieck Gary C,
Mericskay Mathias,
Chini Eduardo N,
Gomez Ana Maria,
Cancela JoséManuel,
Porte Sabine
Publication year - 2022
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202012860
Subject(s) - duchenne muscular dystrophy , cd38 , mdx mouse , ryanodine receptor , nad+ kinase , skeletal muscle , dystrophin , myogenesis , muscular dystrophy , itga7 , medicine , biology , endocrinology , chemistry , microbiology and biotechnology , biochemistry , receptor , stem cell , enzyme , cd34
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.