CD38‐NADase is a new major contributor to Duchenne muscular dystrophic phenotype - CRM - Centre de recherche en myologie - U974 Access content directly
Journal Articles EMBO Molecular Medicine Year : 2022

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

Sonu Kashyap
  • Function : Author
Matthew Fogarty
Gary Sieck
  • Function : Author
Eduardo Chini
  • Function : Author

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.
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hal-03619994 , version 1 (01-06-2022)

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Antoine de Zélicourt, Abdallah Fayssoil, Mbarka Dakouane‐giudicelli, Isley de Jesus, Ahmed Karoui, et al.. CD38‐NADase is a new major contributor to Duchenne muscular dystrophic phenotype. EMBO Molecular Medicine, 2022, 14 (5), pp.e12860. ⟨10.15252/emmm.202012860⟩. ⟨hal-03619994⟩
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