SunnyKabs, the medical world is interesting, that is the reason. I am not working hard, just a hobby. If you read the article below we can almost connect the dots and almost solve the problem of Duchenne. I would think that somebody will soon study if iron overload is the activator of CD38 or reverse ( CD38 activating the development of iron accumulation). So what was missing in the paper above is if CD38 inhibition can be caused by Deferiprone. We know that CD 38 inhibition increases lifespan in mice. ATH434 could be a CD38 inhibitor ???? This reminds me of the unpublished papers of PBT2 (also an iron chelator) in which PBT2 treated animals lived much longer than controls. There are already now speculations that CD38 inhibition could increase also human lifespan.

EMBO Mol Med

. 2022 Mar 17;e12860.

doi: 10.15252/emmm.202012860. Online ahead of print.

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

Antoine de Zélicourt ^{1 2}, Abdallah Fayssoil ¹, Mbarka Dakouane-Giudicelli ¹, Isley De Jesus ¹, Ahmed Karoui ³, Faouzi Zarrouki ¹, Florence Lefebvre ³, Arnaud Mansart ⁴, Jean-Marie Launay ⁵, Jerome Piquereau ³, Mariana G Tarragó ⁶, Marcel Bonay ¹, Anne Forand ^{7 8}, Sophie Moog ^{7 8}, France Piétri-Rouxel ⁷, Elise Brisebard ⁹, Claudia C S Chini ⁶, Sonu Kashyap ⁶, Matthew J Fogarty ⁶, Gary C Sieck ⁶, Mathias Mericskay ³, Eduardo N Chini ⁶, Ana Maria Gomez ³, José-Manuel Cancela ^{# 2}, Sabine de la Porte ^{# 1}

Affiliations expand

• PMID: 35298089

DOI: 10.15252/emmm.202012860

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.