Functional significance of gain-of-function H19 lncRNA in skeletal muscle differentiation and anti-obesity effects.
Functional significance of gain-of-function H19 lncRNA in skeletal muscle differentiation and anti-obesity effects.
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DOI：
10.1186/s13073-021-00937-4
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发表时间：
2021-08-28
期刊：
影响因子：
12.3
通讯作者：
Lin C
中科院分区：
文献类型：
--
作者：
Li Y;Zhang Y;Hu Q;Egranov SD;Xing Z;Zhang Z;Liang K;Ye Y;Pan Y;Chatterjee SS;Mistretta B;Nguyen TK;Hawke DH;Gunaratne PH;Hung MC;Han L;Yang L;Lin C
运动训练是公认的最有效的方法，以提高肌肉性能和肌肉建设。骨骼肌纤维类型的组成影响全身能量消耗，并且代谢稳态的扰动有助于肥胖和其他代谢功能障碍的发生。长链非编码RNA（lncRNA）已被证明在多种细胞过程和疾病（包括人类癌症）中发挥关键作用;然而，lncRNA在肌肉性能、能量平衡和肥胖中的功能重要性仍然难以捉摸。我们先前报道了lncRNA H19调节肌营养不良症中肌营养不良蛋白（DMD）的多聚泛素化和蛋白质稳定性。在这里，我们确定了小鼠/人H19相互作用的蛋白质，使用小鼠/人骨骼肌组织和液相色谱-质谱（LC-MS）。利用来自健康供体和贝克尔肌营养不良症（BMD）患者的人诱导多能干细胞衍生的骨骼肌细胞（iPSC-SkMC）来研究DMD翻译后修饰和相关蛋白。我们鉴定了H19的功能获得性（GOF）突变体，并表征了使用iPSC对成肌细胞分化和融合成肌管的影响。然后，我们将H19 RNA功能获得性寡核苷酸（Rgof）与骨骼肌富集肽聚集蛋白（称为AGR-H19-Rgof）缀合，并使用野生型（WT）C57 BL/6 J小鼠评估AGR-H19-Rgof对骨骼肌性能的作用，以及使用高脂饮食（HFD）和瘦素缺乏诱导的肥胖小鼠模型评估其抗肥胖作用。我们证明人和小鼠H19都与DMD相关，并且与WT H19相比，H19 GOF表现出与DMD的增强的相互作用。在BMD患者的iPSC-SkMC中发现DMD与丝氨酸/苏氨酸蛋白激酶MRCK α（MRCKα）和α-突触核蛋白（SNCA）相关。抑制MRCKα和SNCA介导的DMD磷酸化可拮抗H19与DMD的相互作用。这些信号传导事件导致改善的骨骼肌细胞分化和肌管融合。施用AGR-H19-Rgof改善了WT小鼠的肌肉质量、肌肉性能和基础代谢率。此外，用AGR-H19-Rgof处理的小鼠表现出对HFD或瘦素缺乏诱导的肥胖的抗性。我们的研究表明H19 GOF突变体在增强肌肉性能和抗肥胖作用中的功能重要性。在线版本包含补充材料，可通过10.1186/s13073-021-00937-4获得。
Exercise training is well established as the most effective way to enhance muscle performance and muscle building. The composition of skeletal muscle fiber type affects systemic energy expenditures, and perturbations in metabolic homeostasis contribute to the onset of obesity and other metabolic dysfunctions. Long noncoding RNAs (lncRNAs) have been demonstrated to play critical roles in diverse cellular processes and diseases, including human cancers; however, the functional importance of lncRNAs in muscle performance, energy balance, and obesity remains elusive. We previously reported that the lncRNA H19 regulates the poly-ubiquitination and protein stability of dystrophin (DMD) in muscular dystrophy. Here, we identified mouse/human H19-interacting proteins using mouse/human skeletal muscle tissues and liquid chromatography–mass spectrometry (LC-MS). Human induced pluripotent stem-derived skeletal muscle cells (iPSC-SkMC) from a healthy donor and Becker Muscular Dystrophy (BMD) patients were utilized to study DMD post-translational modifications and associated proteins. We identified a gain-of-function (GOF) mutant of H19 and characterized the effects on myoblast differentiation and fusion to myotubes using iPSCs. We then conjugated H19 RNA gain-of-function oligonucleotides (Rgof) with the skeletal muscle enrichment peptide agrin (referred to as AGR-H19-Rgof) and evaluated AGR-H19-Rgof’s effects on skeletal muscle performance using wild-type (WT) C57BL/6 J mice and its anti-obesity effects using high-fat diet (HFD)- and leptin deficiency-induced obese mouse models. We demonstrated that both human and mouse H19 associated with DMD and that the H19 GOF exhibited enhanced interaction with DMD compared to WT H19. DMD was found to associate with serine/threonine-protein kinase MRCK alpha (MRCKα) and α-synuclein (SNCA) in iPSC-SkMC derived from BMD patients. Inhibition of MRCKα and SNCA-mediated phosphorylation of DMD antagonized the interaction between H19 and DMD. These signaling events led to improved skeletal muscle cell differentiation and myotube fusion. The administration of AGR-H19-Rgof improved the muscle mass, muscle performance, and base metabolic rate of WT mice. Furthermore, mice treated with AGR-H19-Rgof exhibited resistance to HFD- or leptin deficiency-induced obesity. Our study suggested the functional importance of the H19 GOF mutant in enhancing muscle performance and anti-obesity effects. The online version contains supplementary material available at 10.1186/s13073-021-00937-4.
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影响因子：
8.1
作者：
Dyar KA;Ciciliot S;Wright LE;Biensø RS;Tagliazucchi GM;Patel VR;Forcato M;Paz MI;Gudiksen A;Solagna F;Albiero M;Moretti I;Eckel-Mahan KL;Baldi P;Sassone-Corsi P;Rizzuto R;Bicciato S;Pilegaard H;Blaauw B;Schiaffino S
通讯作者：
Schiaffino S
影响因子：
18.4
作者：
Avois, L.;Robinson, N.;Saugy, M.
通讯作者：
Saugy, M.
影响因子：
1.2
作者：
Conner, Jennifer D.;Wolden-Hanson, Tami;Quinn, LeBris S.
通讯作者：
Quinn, LeBris S.
影响因子：
5.4
作者：
Hughes, David C.;Ellefsen, Stian;Baar, Keith
通讯作者：
Baar, Keith
影响因子：
29
作者：
Izumiya, Yasuhiro;Hopkins, Teresa;Walsh, Kenneth
通讯作者：
Walsh, Kenneth