Related Experiment Video
Updated: Sep 30, 2025
Multi-exon Skipping Using Cocktail Antisense Oligonucleotides in the Canine X-linked Muscular Dystrophy
Published on: May 24, 2016
CD38-NADase is a new major contributor to Duchenne muscular dystrophic phenotype
Antoine de Zélicourt1,2, Abdallah Fayssoil1, Mbarka Dakouane-Giudicelli1
1Université Paris-Saclay, UVSQ, Inserm, END-ICAP, Versailles, France.
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.
Insights
CD38 deletion in mdx mice improved heart and skeletal muscle function by restoring nicotinamide adenine dinucleotide (NAD+) levels and reducing inflammation. This suggests CD38 inhibition is a promising therapy for Duchenne muscular dystrophy (DMD).
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Duchenne muscular dystrophy (DMD) involves progressive muscle degeneration, calcium (Ca2+) dysregulation, and deficits in nicotinamide adenine dinucleotide (NAD+).
- CD38, a NAD+ glycohydrolase, influences Ca2+ signaling and is implicated in disease pathology.
Purpose of the Study:
- To investigate the role of CD38 in DMD pathogenesis.
- To evaluate the therapeutic potential of targeting CD38 in DMD models.
Main Methods:
- Deletion of the CD38 gene in mdx mice (mdx/CD38-/-).
- Treatment of mdx and mdx/utrophin-dystrophin-deficient (mdx/utr-/-) mice with CD38 inhibitors.
- Assessment of cardiac and skeletal muscle function, inflammation, senescence markers, and NAD+ levels.
- Treatment of DMD patient-derived myotubes with anti-CD38 antibody (isatuximab).
Main Results:
- CD38 deletion in mdx mice fully restored heart function and structure, improved skeletal muscle performance, reduced inflammation and senescence, and normalized muscle NAD+ levels.
- CD38 inhibition reduced pathological Ca2+ activity in cardiomyocytes from mdx/CD38-/- mice and DMD patient myotubes.
- CD38 inhibitor treatment improved skeletal muscle performance in mdx and mdx/utr-/- mice.
Conclusions:
- CD38 actively contributes to the physiopathology of Duchenne muscular dystrophy.
- Targeting CD38 with specific inhibitors or antibodies presents a potentially effective therapeutic strategy for DMD.
