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microRNA-378 promotes autophagy and inhibits apoptosis in skeletal muscle.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America . 11/13/2018, Vol. 115 Issue 46, pE10849-E10858. 10p. - Publication Year :
- 2018
-
Abstract
- 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 inflammationinduced down-regulation of miR-378 might contribute to the pathogenesis of muscle dystrophy. [ABSTRACT FROM AUTHOR]
- Subjects :
- *MICRORNA
*SKELETAL muscle
*CELL death
*MITOCHONDRIA
*PHOSPHATIDYLINOSITOL 3-kinases
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 115
- Issue :
- 46
- Database :
- Academic Search Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 133027552
- Full Text :
- https://doi.org/10.1073/pnas.1803377115