ATG14 and RB1CC1 play essential roles in maintaining muscle homeostasis.
ATG14 and RB1CC1 play essential roles in maintaining muscle homeostasis.
复制标题
ATG14 和 RB1CC1 在维持肌肉稳态中发挥重要作用。
DOI：
10.1080/15548627.2021.1911549
复制
发表时间：
2021
期刊：
影响因子：
13.3
通讯作者：
Kundu,Mondira
中科院分区：
文献类型：
--
作者：
Li,Dongfang;Vogel,Peter;Li-Harms,Xiujie;Wang,Bo;Kundu,Mondira
大自噬/自噬的缺陷与神经肌肉和心脏疾病的发病机制有关。为了精确定义骨骼肌和心肌中自噬相关基因的作用，我们通过使用Ckm/Ckmm 2-Creand产生肌肉特异性rb 1cc 1-andatg 14-条件性敲除（cKO）小鼠，并将其表型与ulk 1 ulk 2-条件性双敲除（cDKO）小鼠进行比较。atg 14-cKO小鼠发生肥厚性心肌病，这与心脏中自噬物质的异常积累和早期死亡相关。g14-cKO和rb 1cc 1-cKO小鼠的骨骼肌均表现出自噬空泡性肌病的特征，并伴有泛素+SQSTM 1+沉积，但只有rb 1cc 1-cKO小鼠的骨骼肌表现出TARDBP/TDP-43+病理学和我们先前在ulk 1 ulk 2-cDKO小鼠中描述的包涵体肌病样疾病的其他特征。在此，我们强调了骨骼肌和心肌之间在依赖核心自噬蛋白方面的组织特异性差异，以及ULK 1-ULK 2和RB 1CC 1在这些蛋白质中在TARDBP+病理学发展中的独特作用。缩写：AVM：自噬空泡性肌病; cDKO：条件性双敲除; cKO：条件性敲除; H&E：苏木精和伊红; IBM：包涵体肌病; mtDNA：线粒体DNA; PFA：多聚甲醛; RNP：核糖核蛋白; TBST：含0.2%Triton X-100的Tris缓冲盐水
Defects in macroautophagy/autophagy are implicated in the pathogenesis of neuromuscular and heart diseases. To precisely define the roles of autophagy-related genes in skeletal and cardiac muscles, we generated muscle-specificrb1cc1-andatg14-conditional knockout (cKO) mice by usingCkm/Ckmm2-Creand compared their phenotypes to those ofulk1 ulk2-conditional double-knockout (cDKO) mice.atg14-cKO mice developed hypertrophic cardiomyopathy, which was associated with abnormal accumulation of autophagic cargoes in the heart and early mortality. Skeletal muscles of bothatg14-cKO andrb1cc1-cKO mice showed features of autophagic vacuolar myopathy with ubiquitin+SQSTM1+deposits, but only those ofrb1cc1-cKO mice showed TARDBP/TDP-43+pathology and other features of the inclusion body myopathy–like disease we previously described inulk1 ulk2-cDKO mice. Herein, we highlight tissue-specific differences between skeletal and cardiac muscles in their reliance on core autophagy proteins and unique roles for ULK1-ULK2 and RB1CC1 among these proteins in the development of TARDBP+pathology.ABBREVIATIONS:AVM: autophagic vacuolar myopathy; cDKO: conditional double knockout; cKO: conditional knockout; H&E: hematoxylin and eosin; IBM: inclusion body myopathy; mtDNA: mitochondrial DNA; PFA: paraformaldehyde; RNP: ribonucleoprotein; TBST: Tris-buffered saline with 0.2% Triton X-100