PMID- 30373812 OWN - NLM STAT- MEDLINE DCOM- 20190123 LR - 20211204 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 115 IP - 46 DP - 2018 Nov 13 TI - microRNA-378 promotes autophagy and inhibits apoptosis in skeletal muscle. PG - E10849-E10858 LID - 10.1073/pnas.1803377115 [doi] AB - The metabolic regulation of cell death is sophisticated. A growing body of evidence suggests the existence of multiple metabolic checkpoints that dictate cell fate in response to metabolic fluctuations. However, whether microRNAs (miRNAs) are able to respond to metabolic stress, reset the threshold of cell death, and attempt to reestablish homeostasis is largely unknown. Here, we show that miR-378/378* KO mice cannot maintain normal muscle weight and have poor running performance, which is accompanied by impaired autophagy, accumulation of abnormal mitochondria, and excessive apoptosis in skeletal muscle, whereas miR-378 overexpression is able to enhance autophagy and repress apoptosis in skeletal muscle of mice. Our in vitro data show that metabolic stress-responsive miR-378 promotes autophagy and inhibits apoptosis in a cell-autonomous manner. Mechanistically, miR-378 promotes autophagy initiation through the mammalian target of rapamycin (mTOR)/unc-51-like autophagy activating kinase 1 (ULK1) pathway and sustains autophagy via Forkhead box class O (FoxO)-mediated transcriptional reinforcement by targeting phosphoinositide-dependent protein kinase 1 (PDK1). Meanwhile, miR-378 suppresses intrinsic apoptosis initiation directly through targeting an initiator caspase-Caspase 9. Thus, we propose that miR-378 is a critical component of metabolic checkpoints, which integrates metabolic information into an adaptive response to reduce the propensity of myocytes to undergo apoptosis by enhancing the autophagic process and blocking apoptotic initiation. Lastly, our data suggest that inflammation-induced down-regulation of miR-378 might contribute to the pathogenesis of muscle dystrophy. FAU - Li, Yan AU - Li Y AD - State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, 214122 Wuxi, China. AD - Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China. FAU - Jiang, Jingjing AU - Jiang J AD - Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, 200032 Shanghai, China. FAU - Liu, Wei AU - Liu W AD - Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China. FAU - Wang, Hui AU - Wang H AD - Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China. FAU - Zhao, Lei AU - Zhao L AD - Department of Neuromuscular Disease, Children's Hospital of Fudan University, 201102 Shanghai, China. FAU - Liu, Shengnan AU - Liu S AD - Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China. FAU - Li, Peng AU - Li P AD - Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China. FAU - Zhang, Shengjie AU - Zhang S AD - Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China. FAU - Sun, Chao AU - Sun C AD - Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China. FAU - Wu, Yuting AU - Wu Y AD - Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China. FAU - Yu, Shuxian AU - Yu S AD - Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China. FAU - Li, Xihua AU - Li X AD - Department of Neuromuscular Disease, Children's Hospital of Fudan University, 201102 Shanghai, China. FAU - Zhang, Hui AU - Zhang H AD - State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, 214122 Wuxi, China. FAU - Qian, Haifeng AU - Qian H AD - State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, 214122 Wuxi, China. FAU - Zhang, Duo AU - Zhang D AD - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University Medical Campus, Boston, MA 02118. FAU - Guo, Feifan AU - Guo F AD - Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China. FAU - Zhai, Qiwei AU - Zhai Q AD - Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China. FAU - Ding, Qiurong AU - Ding Q AD - Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China. FAU - Wang, Li AU - Wang L AD - State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, 214122 Wuxi, China; wangli@jiangnan.edu.cn yinghao@sibs.ac.cn. FAU - Ying, Hao AU - Ying H AD - Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China; wangli@jiangnan.edu.cn yinghao@sibs.ac.cn. AD - Key Laboratory of Food Safety Risk Assessment, Ministry of Health, 100021 Beijing, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181029 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Forkhead Box Protein O1) RN - 0 (Foxo1 protein, mouse) RN - 0 (MIRN378 microRNA, mouse) RN - 0 (MicroRNAs) RN - EC 2.7.11.1 (3-Phosphoinositide-Dependent Protein Kinases) RN - EC 2.7.11.1 (Autophagy-Related Protein-1 Homolog) RN - EC 2.7.11.1 (Pdpk1 protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.1 (Ulk1 protein, mouse) RN - EC 3.4.22.- (Casp9 protein, mouse) RN - EC 3.4.22.- (Caspase 9) SB - IM MH - 3-Phosphoinositide-Dependent Protein Kinases/metabolism MH - Animals MH - Apoptosis/physiology MH - Autophagy/physiology MH - Autophagy-Related Protein-1 Homolog/metabolism MH - Caspase 9/metabolism MH - Forkhead Box Protein O1/genetics/metabolism MH - Male MH - Mice MH - Mice, Knockout MH - MicroRNAs/genetics/*physiology MH - Muscle Cells/metabolism MH - Muscle, Skeletal/cytology/metabolism/*physiology MH - Running MH - Signal Transduction MH - Stress, Physiological MH - TOR Serine-Threonine Kinases/metabolism PMC - PMC6243236 OTO - NOTNLM OT - apoptosis OT - autophagy OT - miR-378 OT - skeletal muscle COIS- The authors declare no conflict of interest. EDAT- 2018/10/31 06:00 MHDA- 2019/01/24 06:00 PMCR- 2019/05/13 CRDT- 2018/10/31 06:00 PHST- 2018/10/31 06:00 [pubmed] PHST- 2019/01/24 06:00 [medline] PHST- 2018/10/31 06:00 [entrez] PHST- 2019/05/13 00:00 [pmc-release] AID - 1803377115 [pii] AID - 201803377 [pii] AID - 10.1073/pnas.1803377115 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2018 Nov 13;115(46):E10849-E10858. doi: 10.1073/pnas.1803377115. Epub 2018 Oct 29.