microRNA-378 promotes autophagy and inhibits apoptosis in skeletal muscle

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 inflammation-induced down-regulation of miR-378 might contribute to the pathogenesis of muscle dystrophy.

Down-Regulation of miR-378d Increased Rab10 Expression to Help Clearance of Mycobacterium tuberculosis in Macrophages

“…In this study, we have demonstrated that miR-378d plays an important role miR-378d was demonstrated to play a critical role in M. tb-infected macrophages through its target, Rab10, and findings contributed to elucidation of the mechanism underlying miRNA activity in host defense or M. tb pathogenesis during M. tb infection. As introduced previously, miR-378 family members are reported to be induced or inhibited in some tumors and cancers to regulate autophagy (Li et al, 2018b), apoptosis (Costantino et al, 2016;Kuang et al, 2016;Lei et al, 2018;Li et al, 2018b;Ma et al, 2019), cell migration (Ma et al, 2014;Kuang et al, 2016;Templin et al, 2017;Ho et al, 2018), cell proliferation, etc. (Zhang et al, 2017b(Zhang et al, , 2019Li et al, 2018a).…”

Exercise Mediates Heart Protection via Non-coding RNAs

“…MiR-21 targeted and suppressed the peroxisome proliferatoractivated receptor (PPAR) transcript, which regulates plays an important regulatory role in inflammation, ATH, tumors, and fatty acid anabolic, was shown to be increased during HF (Lai et al, 2015;Pinti et al, 2017). Overexpression of miR-378 suppressed ATP synthase F0 subunit 6 (ATP6) and was characterized in the interfibrillar mitochondria amidst diabetes mellitus (Jagannathan et al, 2015;Shepherd et al, 2017;Li et al, 2018). Recent studies showed that cardiopulmonary exercise test was fairly able to elevate the serum levels of miR-21, miR-378, and miR-940 in HF patients (Xu et al, 2016).…”

The role of microvesicles containing microRNAs in vascular endothelial dysfunction

“…It has been estimated that miRNAs regulate the activity of 30%‐50% of protein‐coding genes and modulate about 10%‐30% of human genome expression . miRNAs play a role in regulating various biological processes including metabolism, cell proliferation and differentiation, and apoptosis . The function of miRNA is directly associated with structure; thus, analysing the process of miRNA biogenesis may provide new ideas for the study of miRNA.…”

“…44 miRNAs play a role in regulating various biological processes including metabolism, cell proliferation and differentiation, and apoptosis. [45][46][47] The function of miRNA is directly associated with structure; thus, analysing the F I G U R E 1 The process of MV formation and release from cells. External stimuli followed by increasing intracellular Ca2+ that inhibits the flippase and activates floppase and scramblase with PS movement from the inner face to the outer face of cell membrane.…”