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.

中文翻译：

---

CD38-NADase 是杜氏肌营养不良表型的新主要贡献者。

杜氏肌营养不良症 (DMD) 的特征是进行性肌肉退化。两个重要的有害特征是与兰尼碱受体过度激活相关的 Ca2+ 流入相关的 Ca2+ 失调，以及肌肉烟酰胺腺嘌呤二核苷酸 (NAD+) 缺乏。在这里，我们发现在 mdx 小鼠中缺失 CD38（一种产生 NAD+ 糖水解酶的 Ca2+ 信号传导调节剂）导致心脏功能和结构完全恢复，骨骼肌性能得到改善，与炎症和衰老标志物的减少有关。肌肉 NAD+ 水平也完全恢复，而 CD38 的两种主要产物烟酰胺和 ADP-核糖在心脏、膈肌和四肢中的水平降低。在 mdx/CD38-/- 小鼠的心肌细胞中，病理性自发 Ca2+ 活性降低，以及来自用 isatuximab (SARCLISA®) 单克隆抗 CD38 抗体治疗的 DMD 患者的肌管。最后，用 CD38 抑制剂治疗 mdx 和 utrophin-dystrophin-deficient (mdx/utr-/-) 小鼠导致骨骼肌性能得到改善。因此，我们证明 CD38 积极促成 DMD 生理病理学。我们建议选择性抗 CD38 治疗干预可能与 DMD 患者的开发高度相关。