Increased autophagy and apoptosis contribute to muscle atrophy in a myotonic dystrophy type 1 Drosophila model.
Increased autophagy and apoptosis contribute to muscle atrophy in a myotonic dystrophy type 1 Drosophila model.
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DOI：
10.1242/dmm.018127
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发表时间：
2015-07-01
影响因子：
4.3
通讯作者：
Artero R
中科院分区：
文献类型：
--
作者：
Bargiela A;Cerro-Herreros E;Fernandez-Costa JM;Vilchez JJ;Llamusi B;Artero R
肌肉萎缩是1型强直性肌营养不良（DM 1）疾病最令人衰弱的症状之一，最终导致不动、呼吸缺陷、构音障碍、吞咽困难和疾病晚期死亡。为了研究导致DM1中成人肌肉组织变性损失的分子机制，我们产生了一种类似于成人发病形式的疾病的扩展CTG三核苷酸重复毒性的诱导型果蝇模型。热休克诱导表达的480 CUG重复在成年苍蝇导致间接飞行肌肉的面积减少。在这些模型果蝇中，肌肉面积的减少伴随着细胞凋亡和自噬的增加。抑制由DIAP 1、mTOR（也称为Tor）或肌盲的过表达介导的细胞凋亡或自噬，或通过RNA干扰（RNAi）介导的自噬调节基因沉默，实现了肌肉损失表型的拯救。事实上，mTOR过表达将肌肉大小拯救到与对照果蝇相当的大小。这些结果在DM1患者的骨骼肌活检中得到了验证，我们在其中发现了下调的自噬和凋亡抑制基因，并且在DM1成肌细胞中我们发现了增加的自噬。这些发现为DM1疾病发病机制中涉及的信号通路提供了新的见解。总结：增加的细胞凋亡和自噬是导致DM1中肌肉质量消耗的过程，这是该疾病最令人衰弱的症状之一。
Muscle mass wasting is one of the most debilitating symptoms of myotonic dystrophy type 1 (DM1) disease, ultimately leading to immobility, respiratory defects, dysarthria, dysphagia and death in advanced stages of the disease. In order to study the molecular mechanisms leading to the degenerative loss of adult muscle tissue in DM1, we generated an inducible Drosophila model of expanded CTG trinucleotide repeat toxicity that resembles an adult-onset form of the disease. Heat-shock induced expression of 480 CUG repeats in adult flies resulted in a reduction in the area of the indirect flight muscles. In these model flies, reduction of muscle area was concomitant with increased apoptosis and autophagy. Inhibition of apoptosis or autophagy mediated by the overexpression of DIAP1, mTOR (also known as Tor) or muscleblind, or by RNA interference (RNAi)-mediated silencing of autophagy regulatory genes, achieved a rescue of the muscle-loss phenotype. In fact, mTOR overexpression rescued muscle size to a size comparable to that in control flies. These results were validated in skeletal muscle biopsies from DM1 patients in which we found downregulated autophagy and apoptosis repressor genes, and also in DM1 myoblasts where we found increased autophagy. These findings provide new insights into the signaling pathways involved in DM1 disease pathogenesis. Summary: Increased apoptosis and autophagy are processes that lead to muscle mass wasting in DM1, which is one of the most debilitating symptoms of the disease.
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影响因子：
7.8
作者：
Degtyarev, Michael;De Maziere, Ann;Orr, Christine;Lin, Jie;Lee, Brian B.;Tien, Janet Y.;Prior, Wei W.;van Dijk, Suzanne;Wu, Hong;Gray, Daniel C.;Davis, David P.;Stern, Howard M.;Murray, Lesley J.;Hoeflich, Klaus P.;Klumperman, Judith;Friedman, Lori S.;Lin, Kui
通讯作者：
Lin, Kui
影响因子：
1.5
作者：
García-Casado, Z;Artero, RD;Pérez-Alonso, M
通讯作者：
Pérez-Alonso, M
影响因子：
3.5
作者：
Carmignac, Virginie;Svensson, Martina;Durbeej, Madeleine
通讯作者：
Durbeej, Madeleine
影响因子：
3.7
作者：
Bargiela A;Llamusi B;Cerro-Herreros E;Artero R
通讯作者：
Artero R
影响因子：
1.5
作者：
Hennig, KM;Neufeld, TP
通讯作者：
Neufeld, TP