CD38-NADase is a new major contributor to Duchenne muscular dystrophic phenotype.
CD38-NADase is a new major contributor to Duchenne muscular dystrophic phenotype.
复制标题
DOI：
10.15252/emmm.202012860
复制
发表时间：
2022-05-09
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
杜氏肌营养不良症（DMD）的特征是进行性肌肉变性。两个重要的有害特征是与Ryanodine受体过度激活相关的Ca 2+内流相关的Ca 2+调节失调，以及肌肉烟酰胺腺嘌呤二核苷酸（NAD+）缺乏。在这里，我们确定了mdx小鼠中CD 38（一种产生NAD+糖水解酶的Ca 2+信号调节剂）的缺失，导致心脏功能和结构完全恢复，骨骼肌性能改善，与炎症和衰老标志物减少相关。肌肉NAD+水平也完全恢复，而CD 38的两种主要产物烟酰胺和ADP-核糖的水平在心脏，膈肌和肢体中降低。在mdx/CD 38 −/−小鼠的心肌细胞中，病理性自发Ca 2+活性降低，在接受isatuximab（SARCLISA®）单克隆抗CD 38抗体治疗的DMD患者的肌管中也是如此。最后，用CD 38抑制剂治疗mdx和utrophin-dystrophin-缺陷（mdx/utr-/-）小鼠导致骨骼肌性能改善。因此，我们证明，CD 38积极有助于DMD的病理生理学。我们认为，选择性抗CD 38治疗干预可能与DMD患者的发展高度相关。Duchenne型肌营养不良症（DMD）是以肌肉NAD+缺乏和肌钙超载为特征的疾病。在各种营养不良小鼠模型和人DMD细胞培养物中，我们通过遗传或药理学抑制靶向多功能酶CD 38，这是一种NAD+糖水解酶，可从NAD+产生Ca 2+信号调节剂。
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. Duchenne muscular dystrophy (DMD) is characterized by muscle NAD+ deficit and muscle Ca2+ overload. In various dystrophic mouse models and a human DMD cell culture, we have targeted the multifunctional enzyme CD38, a NAD+ glycohydrolase that generates Ca2+ signaling modulators from NAD+, by genetic or pharmacological inhibition.
登录
查看更多内容
影响因子：
3.3
作者：
Consolino, CM;Brooks, SV
通讯作者：
Brooks, SV
影响因子：
20.8
作者：
Chini CCS;Peclat TR;Warner GM;Kashyap S;Espindola-Netto JM;de Oliveira GC;Gomez LS;Hogan KA;Tarragó MG;Puranik AS;Agorrody G;Thompson KL;Dang K;Clarke S;Childs BG;Kanamori KS;Witte MA;Vidal P;Kirkland AL;De Cecco M;Chellappa K;McReynolds MR;Jankowski C;Tchkonia T;Kirkland JL;Sedivy JM;van Deursen JM;Baker DJ;van Schooten W;Rabinowitz JD;Baur JA;Chini EN
通讯作者：
Chini EN
DOI：
10.1016/j.bbrc.2019.03.199
发表时间：
2019-05-28
影响因子：
3.1
作者：
Chini, Claudia;Hogan, Kelly A.;Chini, Eduardo
通讯作者：
Chini, Eduardo
影响因子：
29
作者：
Camacho-Pereira J;Tarragó MG;Chini CCS;Nin V;Escande C;Warner GM;Puranik AS;Schoon RA;Reid JM;Galina A;Chini EN
通讯作者：
Chini EN
影响因子：
13.8
作者：
Chini EN;Chini CCS;Espindola Netto JM;de Oliveira GC;van Schooten W
通讯作者：
van Schooten W