Patterson Dalton C, Birnbaum Allison, Matthews Ian, Cortes Constanza J
Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA, USA.
bioRxiv. 2025 May 28:2025.05.28.655862. doi: 10.1101/2025.05.28.655862.
Endurance exercise (running) promotes skeletal muscle remodeling through metabolic and inflammatory signaling cascades. However, the extent to which these responses are sex-dependent remains unclear. Here, we profiled cytokine responses in quadriceps muscle lysates from sedentary, voluntary wheel-running (VWR; 5 weeks), and muscle-specific TFEB-overexpressing (cTFEB;HSACre) male and female mice. Cytokine analysis revealed 40 differentially expressed factors associated with exercise and/or TFEB overexpression, many displaying sex-dimorphic expression patterns. In males, VWR induced significant increases in interleukins (e.g., IL-1α, IL-1β, IL-2, IL-5, IL-17) and chemokines (e.g., MCP-1, CCL5, CXCL9), as well as cytokines involved in TNF signaling (e.g., TNFα, sTNFR1/2, Fas ligand). TFEB overexpression in sedentary males recapitulated many of these cytokine elevations. In contrast, female runner muscle showed limited cytokine activation, with significant changes restricted to IL-3, IL-3Rb, IL-13, and CXCL16. Both sexes exhibited a reduction in IL-4 and an increase in IGFBP-5 with running. Several additional male-specific cytokine profiling responses, including increases in IFNγ, SCF, TPO, VCAM1A, and leptin, further underscored the sex-specificity of exercise-related inflammatory adaptations. These findings demonstrate that skeletal muscle cytokine responses to endurance-like stimuli are profoundly influenced by sex and suggest that male muscle exhibits a broader and/or later remodeling profile than female muscle. Our data also implicate skeletal muscle TFEB-overexpression as a partial molecular mediator of the cytokine shifts observed with exercise, particularly in males, and highlights their potential use as a new prioritization platform for exercise-associated phenotypes.
耐力运动（跑步）通过代谢和炎症信号级联反应促进骨骼肌重塑。然而，这些反应在多大程度上依赖性别仍不清楚。在此，我们分析了久坐不动、自愿轮转跑步（VWR；5周）以及肌肉特异性转录因子EB（TFEB）过表达（cTFEB；HSACre）的雄性和雌性小鼠股四头肌裂解物中的细胞因子反应。细胞因子分析揭示了40种与运动和/或TFEB过表达相关的差异表达因子，其中许多呈现出性别二态性表达模式。在雄性小鼠中，VWR诱导白细胞介素（如IL-1α、IL-1β、IL-2、IL-5、IL-17）和趋化因子（如MCP-1、CCL5、CXCL9）以及参与肿瘤坏死因子（TNF）信号传导的细胞因子（如TNFα、sTNFR1/2、Fas配体）显著增加。久坐雄性小鼠中TFEB过表达重现了许多这些细胞因子的升高。相比之下，雌性跑步小鼠肌肉的细胞因子激活有限，显著变化仅限于IL-3、IL-3Rb、IL-13和CXCL16。跑步时，两性均表现出IL-4减少和IGFBP-5增加。其他一些雄性特异性细胞因子谱反应，包括IFNγ、SCF、TPO、VCAM1A和瘦素增加，进一步强调了运动相关炎症适应的性别特异性。这些发现表明，骨骼肌对耐力样刺激的细胞因子反应受到性别的深刻影响，并表明雄性肌肉比雌性肌肉表现出更广泛和/或更晚的重塑特征。我们的数据还表明，骨骼肌TFEB过表达是运动时观察到的细胞因子变化的部分分子介质，特别是在雄性中，并突出了它们作为运动相关表型新的优先排序平台的潜在用途。
