de Calbiac Hortense, Montealegre Sebastian, Straube Marjolène, Renault Solène, Debruge Hugo, Chentout Loïc, Ciura Sorana, Imbard Apolline, Guillou Edouard Le, Marian Anca, Goudin Nicolas, Caccavelli Laure, Fabrega Sylvie, Hubas Arnaud, van Endert Peter, Dupont Nicolas, Diana Julien, Kabashi Edor, de Lonlay Pascale
Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France.
Reference Center of Inherited Metabolic Diseases, Hôpital Universitaire Necker-Enfants Malades, AP-HP, Institut Imagine, Filière G2M, MetabERN, F-75015, Paris, France.
Autophagy Rep. 2024 Feb 1;3(1). doi: 10.1080/27694127.2024.2306766. eCollection 2024 Dec 31.
Patients with pathogenic variants in the gene suffer from severe and recurrent rhabdomyolysis episodes precipitated by fasting. Autophagy functioning was analyzed , in primary skeletal myoblasts from TANGO2 patients, in basal and fasting conditions, and mutations were associated with reduced LC3-II levels upon starvation. In zebrafish larvae, inhibition induced locomotor defects which were exacerbated by exposure to atorvastatin, a compound known to cause rhabdomyolysis. Importantly, rhabdomyolysis features of knockdown were associated with autophagy and mitophagy defects in zebrafish. Calpeptin treatment was sufficient to rescue the locomotor properties thanks to its beneficial effect on autophagy functioning in zebrafish and to improve LC3-II levels in starved primary muscle cells of TANGO2 patients. Overall, we demonstrated that TANGO2 plays an important role in autophagy thus giving rise to new therapeutic perspectives in the prevention of RM life-threatening episodes.
该基因存在致病变异的患者会因禁食引发严重且反复发作的横纹肌溶解症。研究分析了TANGO2患者原代骨骼肌成肌细胞在基础状态和禁食条件下的自噬功能，发现相关突变与饥饿时LC3-II水平降低有关。在斑马鱼幼虫中，该基因抑制会导致运动缺陷，而阿托伐他汀（一种已知会引起横纹肌溶解的化合物）暴露会加剧这种缺陷。重要的是，该基因敲低的横纹肌溶解特征与斑马鱼的自噬和线粒体自噬缺陷有关。钙蛋白酶抑制剂治疗足以挽救运动特性，这得益于其对斑马鱼自噬功能的有益作用，并提高了TANGO2患者饥饿原代肌肉细胞中的LC3-II水平。总体而言，我们证明了TANGO2在自噬中起重要作用，从而为预防危及生命的横纹肌溶解发作带来了新的治疗前景。
