Formononetin ameliorates muscle atrophy by regulating myostatin‐mediated PI3K/Akt/FoxO3a pathway and satellite cell function in chronic kidney disease

Abstract

Muscle atrophy is a common complication in chronic kidney disease (CKD). Inflammation and myostatin play important roles in CKD muscle atrophy. Formononetin (FMN), which is a major bioactive isoflavone compound in Astragalus membranaceus , exerts anti‐inflammatory effects and the promotion of myogenic differentiation. Our study is based on myostatin to explore the effects and mechanisms of FMN in relation to CKD muscle atrophy. In this study, CKD rats and tumour necrosis factor α (TNF‐α)‐induced C2C12 myotubes were used for in vivo and in vitro models of muscle atrophy. The results showed that FMN significantly improved the renal function, nutritional status and inflammatory markers in CKD rats. Values for bodyweight, weight of tibialis anterior and gastrocnemius muscles, and cross‐sectional area (CSA) of skeletal muscles were significantly larger in the FMN treatment rats. Furthermore, FMN significantly suppressed the expressions of MuRF‐1, MAFbx and myostatin in the muscles of CKD rats and the TNF‐α‐induced C2C12 myotubes. Importantly, FMN significantly increased the phosphorylation of PI3K, Akt, and FoxO3a and the expressions of the myogenic proliferation and differentiation markers, myogenic differentiation factor D (MyoD) and myogenin in muscles of CKD rats and the C2C12 myotubes. Similar results were observed in TNF‐α‐induced C2C12 myotubes transfected with myostatin‐small interfering RNA (si‐myostatin). Notably, myostatin overexpression plasmid (myostatin OE) abolished the effect of FMN on the phosphorylation of the PI3K/Akt/FoxO3a pathway and the expressions of MyoD and myogenin. Our findings suggest that FMN ameliorates muscle atrophy related to myostatin‐mediated PI3K/Akt/FoxO3a pathway and satellite cell function.

Polyphenols and Their Effects on Muscle Atrophy and Muscle Health

“…In formononetin-treated mice, body weight, the weight of the tibialis anterior and GM, and the CSA of skeletal muscles were significantly improved compared with CKD mice. Moreover, it effectively suppressed MuRF-1, MAFbx, and myostatin expression in TNF-α-induced cells and CKD-mice, whereas the phosphorylation of PI3K, Akt, and Foxo3a was enhanced by formononetin in both in vitro and in vivo models [ 94 ]. Glabridin, which is a prenylated isoflavone, inhibited Dex-induced protein degradation in C2C12 myotubes and in the tibialis anterior muscle of mice through the suppression of the ubiquitin ligases MuRF1 and Cbl-b but not atrogin-1.…”

Cardiomyocyte Atrophy, an Underestimated Contributor in Doxorubicin-Induced Cardiotoxicity

“…Phosphoinositide 3-kinase-AKT activation promotes FOXOs to transport from nucleus to cytoplasm, where FOXOs are sequestered by 14-3-3 proteins and stay inactive (102). Several studies have revealed that the inhibition of PI3K-AKT signaling pathway promoted muscle atrophy via FOXOs-mediated activation of UPS (103)(104)(105). Moreover, Spurthi et al reported that toll-like receptor 2 deficiency suppressed PI3K-AKT and activated FOXO1-atrogin-1/MuRF1, which resulted into cardiac atrophy in aging mice (106).…”

Paeoniflorin Ameliorates Skeletal Muscle Atrophy in Chronic Kidney Disease via AMPK/SIRT1/PGC-1α-Mediated Oxidative Stress and Mitochondrial Dysfunction

“…# p < 0.05, ## p < 0.01, ### p < 0.001 compared with the TNF + NC-siRNA group; & p < 0.05, && p < 0.01, &&& p < 0.001 compared with the TNF + PF + NC-siRNA group; % p < 0.05, % % p < 0.01, %%% p < 0.001 compared with the Control PGC-1α-siRNA group. performance were determined as direct indicators of muscle atrophy in CKD model rats based on our previous studies (Wang et al, 2019;Hu et al, 2020;Liu et al, 2021). The PFtreated group was confirmed by an increase in body weight, muscle weight and muscle fiber CSA.…”

“…The nephrectomized group rats underwent a 5/6 nephrectomy surgical resection of the upper and lower thirds of the left kidney and were subjected to right nephrectomy after 1 week. The Sham group rats were treated as described previously ( Wang et al, 2019 ; Hu et al, 2020 ; Liu et al, 2021 ). Rats were observed postprocedure for 1–2 h, and their wound healing, movements, mental states and body weights were monitored weekly.…”