AMPK agonists(Peking Union Medical College Hospital)

ELABELA (ELA) has been identified as a potential cardiovascular protective factor. However, the source of endogenous ELA and its molecular mechanism in myocardial fibrosis inhibition remain incompletely understood. Herein, we found that aerobic exercise significantly improved renal apoptosis caused by MI, inhibited inflammation, attenuated structural damage, enhanced renal function, and increased expression and secretion levels of renal ELA. Aerobic exercise stimulated the circulation of renal‐derived ELA to reach the MI heart and played a protective role. Under aerobic exercise intervention, renal‐specific Elabela overexpression improved myocardial pathological remodeling, decreased cardiomyocyte apoptosis, and enhanced cardiac function. Renal‐specific Elabela knockdown significantly increased cardiac apoptosis, inflammation, and fibrosis levels in MI mice, leading to severe impairment of cardiac function. Following AMPK agonist intervention, ELA expression in HKC cells and culture medium increased in a concentration‐dependent manner. ELA‐14 significantly activated the APJ‐AMPK‐Sirt1 signaling pathway and inhibited Tgf‐β1 transcription by regulating Sirt1 translocation, and AMPK inhibitor weakened ELA‐14 function. In cultured cardiac fibroblasts (CFs), the intervention of ELA‐14 significantly inhibited the activity of the TGFβ1‐Smad2/3 signaling pathway, downregulated the expression of fibrosis‐related proteins, increased apoptosis, and lowered the cell migration rate. After TGFβR1 inhibitor intervention, ELA‐14 showed a loss of regulation of CFs. Aerobic exercise stimulates the expression of renal‐derived ELA, which reaches the MI heart through blood circulation. Renal‐derived ELA partly exerts its antifibrotic effects by activating the APJ‐AMPK‐Sirt1 pathway and inhibiting the TGFβ1‐Smad2/3 signaling pathway, contributing to its cardiac protective effects.

Mitochondrial ORF of the 12S rRNA type-c (MOTS-c) as an AMPK agonist can regulate the expression of adaptive nuclear genes to promote cell homeostasis. However, the investigation of MOTS-c in hepatocellular carcinoma (HCC) is insufficient. This study aims to reveal the role of MOTS-c on HCC cell apoptosis.

Huh7 and HCCLM3 cells were incubated with MOTS-c under a hypoxic condition. MOTS-c levels were quantified by enzyme-linked immunosorbent assay in the peripheral blood of HCC patients and healthy controls. Cell viability was detected by 3-(4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell apoptosis was investigated by flow cytometry and Tunel assay. Protein expression was detected by western blotting or immunohistochemistry assay. Dual-luciferase reporter assay and chromatin immunoprecipitation assay were performed to identify the association among myocyte enhancer factor 2A (MEF2A), death receptor 4 (DR4) and DR5. A tumor-bearing nude mouse model was conducted to assess the effect of MOTS-c on HCC tumor formation in vivo.

MOTS-c levels in the peripheral blood of HCC patients were significantly lower compared to healthy individuals. MOTS-c promoted HCC cell apoptosis under hypoxia conditions. Hypoxia stimulation decreased the protein expression of MEF2A, DR4, DR5, fas-associating via death domain (FADD) and caspase-8, while these effects were attenuated after MOTS-c treatment. MOTS-c induced TRAIL-induced apoptosis of HCC cells by activating MEF2A through the phosphorylation of AMPK under hypoxia treatment. In addition, MEF2A transcriptionally up-regulated DR4 and DR5. MOTS-c activated MEF2A to regulate DR4 and DR5 expression, further mediating TRAIL-induced apoptosis. Further, MOTS-c treatment relieved hypoxia-induced tumor growth in vivo.

MOTS-c relieved hypoxia-induced HCC cell resistance to TRAIL-caused apoptosis by activating MEF2A.