Shi Luze, Ding Zheci, Chen Jiwu
Department of Sports Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Front Pharmacol. 2025 Mar 12;16:1557703. doi: 10.3389/fphar.2025.1557703. eCollection 2025.
Sarcopenia is a condition characterized by the loss of muscle fibers and excessive deposition of extracellular matrix proteins. The interplay between muscle atrophy and fibrosis is a central feature of sarcopenia. While the mechanisms underlying skeletal muscle aging and fibrosis remain incompletely understood, cellular senescence has emerged as a key contributor. This study investigates the role of D-galactose (D-gal) in inducing fibroblasts senescence and skeletal muscle fibrosis, and aims to find the key regulator of the process to serve as a therapeutical target.
To discover the role of D-gal in inducing cellular senescence and fibrosis, the senescence markers and the expression of fibrosis-related proteins were assessed after introducing D-gal among fibroblasts, and muscle strength and mass. The severity of muscle atrophy and fibrosis were also verified by using H&E staining and Masson trichrome staining after D-gal treatment via subcutaneous injection among mice. Subsequently, mRNA sequencing (RNA-seq) was performed and the differential expressed genes were identified between under D-gal or control treatment, to discover the key regulator of D-GAL-driven fibroblasts senescence and fibrosis. The role of the key regulator IGFBP5 were then validated in D-GAL treated IGFBP5-knockdown fibroblasts by analyzing the level of senescence and fibrosis-related markers. And the results were further confirmed in IGFBP5-knockdown SAMP8 mice with histological examinations.
D-gal treatment effectively induced cellular senescence and fibrosis in fibroblasts, as well as skeletal muscle atrophy, fibrosis and loss in muscle mass and function in mice. IGFBP5 was identified as a key regulator of D-GAL induced senescence and fibrosis among fibroblasts using RNA-seq. And further validation tests showed that IGFBP5-knockdown could alleviate D-GAL-induced fibroblast cellular senescence and fibrosis, as well as the severity of muscle atrophy and fibrosis in SAMP8 mice.
IGFBP5 emerging as a key regulator of D-GAL-induced fibroblast cellular senescence and fibrosis. The findings provide new insights into the molecular mechanisms underlying age-related skeletal muscle fibrosis and highlight IGFBP5 as a potential therapeutic target. Further research is needed to validate these findings and explore related clinical applications.
肌肉减少症是一种以肌纤维丢失和细胞外基质蛋白过度沉积为特征的病症。肌肉萎缩与纤维化之间的相互作用是肌肉减少症的核心特征。虽然骨骼肌衰老和纤维化的潜在机制仍未完全了解，但细胞衰老已成为一个关键因素。本研究调查了D-半乳糖（D-gal）在诱导成纤维细胞衰老和骨骼肌纤维化中的作用，旨在找到该过程的关键调节因子作为治疗靶点。
为了发现D-gal在诱导细胞衰老和纤维化中的作用，在成纤维细胞中引入D-gal后评估衰老标志物和纤维化相关蛋白的表达，以及肌肉力量和质量。通过在小鼠皮下注射D-gal进行处理后，使用苏木精-伊红（H&E）染色和马松三色染色来验证肌肉萎缩和纤维化的严重程度。随后，进行mRNA测序（RNA-seq），并鉴定D-gal处理组与对照组之间的差异表达基因，以发现D-GAL驱动的成纤维细胞衰老和纤维化的关键调节因子。然后通过分析衰老和纤维化相关标志物的水平，在D-GAL处理的IGFBP5基因敲低的成纤维细胞中验证关键调节因子IGFBP5的作用。并通过组织学检查在IGFBP5基因敲低的SAMP8小鼠中进一步证实结果。
D-gal处理有效地诱导了成纤维细胞的细胞衰老和纤维化，以及小鼠的骨骼肌萎缩、纤维化和肌肉质量与功能丧失。使用RNA-seq鉴定出IGFBP5是D-GAL诱导成纤维细胞衰老和纤维化的关键调节因子。进一步的验证试验表明，敲低IGFBP5可以减轻D-GAL诱导的成纤维细胞衰老和纤维化，以及SAMP8小鼠的肌肉萎缩和纤维化严重程度。
IGFBP5成为D-GAL诱导的成纤维细胞衰老和纤维化的关键调节因子。这些发现为与年龄相关的骨骼肌纤维化的分子机制提供了新的见解，并突出了IGFBP5作为潜在治疗靶点的地位。需要进一步的研究来验证这些发现并探索相关的临床应用。
