Department of Environmental Health, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, PR China.
Department of Environmental Health, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, PR China.
Ecotoxicol Environ Saf. 2023 Mar 1;252:114626. doi: 10.1016/j.ecoenv.2023.114626. Epub 2023 Feb 8.
Excess intake of fluoride leads to a serious health issue called fluorosis. Fluorosis patients exhibit the symptom of muscle damage, but the specific mechanism remains unclear. Fibroblast growth factor 21 (FGF21) is a novel myokine that is involved in the regulation of myogenic differentiation, but whether fluoride induces skeletal muscle damage via FGF21 signaling has not been reported yet. In the current study, C2C12 cells were used to investigate the impact of fluoride on myogenic development and the involved regulatory role of FGF21/ERK signaling pathway. The expressions of the markers of myoblasts development and FGF21/ERK signaling pathway-related molecules were detected after fluoride treatment. The results indicated that fluoride notably inhibited the expressions of myogenic regulatory genes MyoD, MyoG and MyHC in C2C12 cells. In addition, fluoride increased the expressions of muscle atrophy-related markers MuRF1 and MAFbx. We proved that fluoride significantly inhibited the expression of FGF21 based on the RNA-seq results, and detected the expressions of downstream molecules FGFR1, KLB, Raf, MEK and ERK. Moreover, FGF21 pretreatment reversed the adverse effect of fluoride on the C2C12 cells and alleviated the atrophy of myotubes. Taken together, these findings indicated that fluoride suppressed differentiation and aggravated atrophy via FGF21/ERK signaling pathway in C2C12 cells. Our study has provided new evidence for the role of FGF21/ERK in fluoride-induced skeletal muscle damage and FGF21 may be one of the potential targets for prevention and treatment of fluorosis.
过量摄入氟会导致一种严重的健康问题，称为氟中毒。氟中毒患者表现出肌肉损伤的症状，但具体机制尚不清楚。成纤维细胞生长因子 21（FGF21）是一种新型的肌因子，参与肌生成分化的调节，但氟是否通过 FGF21 信号诱导骨骼肌损伤尚未有报道。在本研究中，使用 C2C12 细胞研究氟对肌生成发育的影响以及 FGF21/ERK 信号通路的参与调节作用。用氟化物处理后检测成肌细胞发育和 FGF21/ERK 信号通路相关分子的标志物的表达。结果表明，氟化物明显抑制 C2C12 细胞中肌调节基因 MyoD、MyoG 和 MyHC 的表达。此外，氟化物增加了肌肉萎缩相关标记物 MuRF1 和 MAFbx 的表达。我们基于 RNA-seq 结果证明了氟化物显著抑制了 FGF21 的表达，并检测了下游分子 FGFR1、KLB、Raf、MEK 和 ERK 的表达。此外，FGF21 预处理逆转了氟化物对 C2C12 细胞的不良影响，并减轻了肌管的萎缩。总之，这些发现表明氟化物通过 FGF21/ERK 信号通路抑制分化并加重 C2C12 细胞中的萎缩。我们的研究为 FGF21/ERK 在氟诱导的骨骼肌损伤中的作用提供了新的证据，并且 FGF21 可能是预防和治疗氟中毒的潜在靶点之一。
