MicroRNA-140 inhibits skeletal muscle glycolysis and atrophy in endotoxin-induced sepsis in mice via the WNT signaling pathway

Abstract

Sepsis is a systemic inflammatory response syndrome resulting from infection. This study aimed at exploring the role of microRNA-140 (miR-140) in septic mice. Wnt family member 11 (WNT11) was verified to be a target gene of miR-140 after bioinformatic prediction and dual luciferase reporter gene assay. Importantly, miR-140 negatively regulated WNT11. We initially induced the model of sepsis by endotoxin, and then ectopic expression and knockdown experiments were performed to explore the functional role of miR-140 in sepsis. Additionally, cross-sectional areas of muscle fiber, lactic acid production, 3-methylhistidine (3-MH) and tyrosine (Tyr) production in extensor digitorium longus (EDL) muscles, and serum levels of inflammatory factors were examined. The effect of miR-140 on the expression of WNT signaling pathway-related and apoptosis-related factors in skeletal muscle tissue was determined. The experimental results indicated that upregulated miR-140 or silenced WNT11 increased cross-sectional areas of muscle fiber while decreasing lactic acid production, skeletal muscle cell apoptosis [corresponding to downregulated B cell lymphoma 2 (Bcl-2)-associated X protein (Bax) and caspase-3 and upregulated Bcl-2], and the proteolytic rate of Tyr and 3-MH. Also, overexpressed miR-140 or silenced WNT11 reduced inflammation as reflected by decreased serum levels of IL-6, IL-10, and TNF-α. Furthermore, overexpression of miR-140 was shown to suppress the activation of the WNT signaling pathway, accompanied by decreased expression of WNT11, β-catenin, and GSK-3β. Taken together, upregulation of miR-140 could potentially inhibit skeletal muscle lactate release, an indirect measure of glycolysis, and atrophy in septic mice through suppressing the WNT signaling pathway via inhibiting WNT11 expression.

Glycogen Synthase Kinase-3β Inhibitor Lithium Chloride Protects Against Inflammation-Mediated Skeletal Muscle Wasting

“…Prior to evaluate the effect on cancer cachexia, we veri ed the phenotype of LiCl on myogenic differentiation. As expected, treatment of LiCl reduced the expression of paired box protein Pax-7 (a myoblast marker indicating myotube dedifferentiation 46,47 ) while increasing the expression Myh2 (a myotube marker 2 ) ( Figure 1A-B). CCM has been shown to contain factors that inhibit both myoblast proliferation and myogenic differentiation 29 .…”

“…This is also supported by our data showing that targeting the secondary biological target of LiCl, IMPase, using the chemical inhibitor, ebselen, did not prevent CCM-induced myotube wasting in vitro 33,46 . There are numerous reports of role of GSK-3β inhibition in myotube differentiation and atrophy in vivo and in vitro [47][48][49][50] . We believe that the signi cance of our study is the demonstration that a clinically approved GSK-3β inhibitor (LiCl) can prevent in ammation mediated myotube atrophy in animal models.…”

NR2F1-AS1/miR-140/HK2 Axis Regulates Hypoxia-Induced Glycolysis and Migration in Hepatocellular Carcinoma

“… 33 In addition, miR-140 was reported to repress glycolysis in sepsis and breast cancer. 34 , 35 Similarly, we also found the anti-migration and anti-glycolysis roles of miR-140 in HCC under hypoxia, revealed via which miR-140 knockdown reversed the anti-cancer role of NR2F1-AS1 in HCC.…”

Bie Jia Jian pill enhances the amelioration of bone mesenchymal stem cells on hepatocellular carcinoma progression

“…Further detection on the downstream signal pathway of miR-140 showed that Wnt/β-catenin signal pathway was suppressed in response to BJJP or BMSCs treatment, while suppression on miR-140 could reverse the suppression of BJJP and BMSCs in Wnt/β-catenin signal pathway. The regulation of miR-140 on Wnt/β-catenin signal pathway can be found in both carcinoma tissues and other diseases, including lung cancer, malignant melanoma, nasopharynx cancer and sepsis [26][27][28][29]. Taken together, those results showed that BJJP and BMSCs could elevate miR-140 expression, which in turn could suppress the activation of Wnt/β-catenin signal pathway.…”