Upregulation of microRNA‐351 exerts protective effects during sepsis by ameliorating skeletal muscle wasting through the Tead‐4‐mediated blockade of the Hippo signaling pathway

Abstract

Sepsis-induced skeletal muscle wasting may lead to various severe clinical consequences. Understanding molecular mechanisms of the regulation of the loss of skeletal muscle mass in septic patients remains a significant clinical challenge. The current study was conducted to establish septic mice models to explore the relationship between microRNA (miR)-351 and the transcription element apical (TEA) domain transcription factor (Tead)-4 gene and to investigate its effects on the skeletal muscle through mediating the Hippo signaling pathway in mice with acute sepsis. A total of 60 mice were collected to establish mouse models of acute sepsis. The positive expression rate of Tead-4 and the apoptotic index (AI) were measured. A dual-luciferase reporter gene assay was conducted to verify the targeting relationship between miR-351 and Tead-4. Furthermore, the muscle fiber diameter (MFD) and area (MFA) and the content of 3-methylhistidine (3-MH) and tyrosine (Tyr) were assessed. The expression levels of miR-351, p38-MAPK, Yes-associated protein, Tead-4, B-cell lymphoma X protein (Bax), and Caspase-3 were determined with quantitative RT-PCR and Western blot analysis. Finally, cell viability, apoptosis, and levels of inflammatory factors, including IL-1β, IL-6, IGF-1, TNF-α, and monocyte chemoattractant protein-1 were detected by 3-(4,5-dimethylthiazol-2- yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, and ELISA. Initially, Tead-4 protein expression was higher in skeletal muscle tissues of mice with acute sepsis. Tead-4 was identified to negatively regulate miR-351. Upregulation of miR-351 increased MFA and MFD, muscle weight water content, Bcl-2 expression levels, and cell viability. Up-regulation of miR-351 reduced AI; 3-MH and Tyr content; positive expression of Tead-4 protein; the expression levels of p38-MAPK, Yap, Tead-4, Bax, and Caspase-3; apoptosis; and inflammatory responses. The current study demonstrated that up-regulation of miR-351 inhibits the degradation of skeletal muscle protein and the atrophy of skeletal muscle in mice with acute sepsis by targeting Tead-4 through suppression of the Hippo signaling pathway. Thus, miR-351 overexpression may be a future therapeutic strategy for acute sepsis.-Zhang, L.-N., Tian, H., Zhou, X.-L., Tian, S.-C., Zhang, X.-H., Wu, T.-J. Upregulation of microRNA-351 exerts protective effects during sepsis by ameliorating skeletal muscle wasting through the Tead-4-mediated blockade of the Hippo signaling pathway.

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

“…Another study also demonstrated the interaction between miR-140 -5p and the WNT/␤-catenin signaling pathway, suggesting that miR-140 -5p could inactivate the WNT/␤-catenin signaling pathway by binding to WNT1 gene, thereby suppressing the hypoxic-ischemic brain damage (7). As a previous study reported by Zhang et al, the upregulation of miR-351 could attenuate acute sepsis in mice by reducing the degradation of skeletal muscle protein and skeletal muscle atrophy by regulation of the target gene Tead-4 via inactivation of the Hippo signaling pathway (32). For the present study, apart from the effect of miR on skeletal muscle atrophy, production of Tyr and 3-MH, Bcl-2 expression, and skeletal muscle apoptosis, we further explored the effects of miR-140 on muscle fiber cross-sectional areas and lactic acid production to thoroughly confirm the inhibitory role of miR-140 in endotoxin-treated mice.…”

lncRNA MALAT1 Accelerates Skeletal Muscle Cell Apoptosis and Inflammatory Response in Sepsis by Decreasing BRCA1 Expression by Recruiting EZH2

“…The remaining 80 mice were used to establish sepsis models, and the success rate was 67.5%. The mouse model of sepsis was established as previously reported 31 . In short, the mice were anesthetized with 3% sodium pentobarbital (no.…”

ACSL4 contributes to ferroptosis‐mediated rhabdomyolysis in exertional heat stroke

“…Additionally, ferroptosis activation has been reported to induce acute kidney failure and early death in mice caused by the disruption of GPX4 26 . In addition, a recent study demonstrated that ferroptosis is involved in RM associated kidney damage in vivo and in vitro 32 . RM causes the release of MB and other muscle cell components to the bloodstream.…”

“…RM causes the release of MB and other muscle cell components to the bloodstream. MB is freely filtered by glomeruli and reabsorbed by proximal tubules, promoting ferroptosis‐mediated cell death, thus leading to AKI, the treatment of Fer‐1 strongly inhibits the severity of AKI via decreasing the MB‐derived iron accumulation and lipid peroxidation 32 . This is consistent with the results in current study, RM following the EHS could induce remarkable AKI and the severity of AKI induced by the RM after EHS were strongly ameliorated by the Fer‐1 administration in vivo .…”