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 mouse 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. FASEB J. 32, 6934–6947 (2018). www.fasebj.org