Convergent skeletal muscle cytokine responses to TFEB overexpression and voluntary wheel running reflect sex‐based variability to exercise adaptations in mice

• Published in: Physiological reports Vol. 13; no. 16
• Main Authors: Patterson, Dalton C., Birnbaum, Allison, Matthews, Ian, Cortes, Constanza J.
• Format: Journal Article
• Language: English
• Published: Oxford John Wiley & Sons, Inc 01.08.2025; John Wiley and Sons Inc
• Subjects: Chemokines; CXCL16 protein; Cytokines; Exercise; Exercise and Diet; FasL protein; Females; Fitness equipment; Inflammation; Ligands; Lysates; Males; Metabolism; Musculoskeletal system; Original; Phenotypes; Phosphorylation; Physical fitness; Proteins; Quadriceps muscle; Running; Sex; Sexes; sex‐differences; Skeletal muscle; Transgenic animals; Tumor necrosis factor-TNF; Wheel running
• ISSN: 2051-817X
• DOI: 10.14814/phy2.70519

Running promotes skeletal muscle remodeling through metabolic and inflammatory signaling pathways, though the extent to which these responses are sex‐dependent remains unclear. We profiled cytokine responses in quadriceps lysates from sedentary, voluntary wheel‐running (VWR), 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 exhibiting sex‐dimorphic patterns. In males, VWR increased interleukins (IL‐1α, IL‐1β, IL‐2, IL‐5, and IL‐17) and chemokines (e.g., MCP‐1, CCL5, and CXCL9), including components of TNF signaling (e.g., TNFα, sTNFR1/2, and Fas ligand). These elevations were partially recapitulated by TFEB overexpression in sedentary males. In contrast, female VWR muscle showed limited changes, with significant differences restricted to IL‐3, IL‐3Rb, IL‐13, and CXCL16. These findings demonstrate sex‐specific cytokine responses to endurance‐like stimuli and suggest a broader or more prolonged inflammatory remodeling profile in male skeletal muscle. Moreover, muscle‐specific TFEB overexpression reproduced similar endurance‐induced cytokine changes, particularly in males, highlighting TFEB as a partial molecular mimic of exercise‐associated inflammatory signaling in skeletal muscle. Together, our data underscore the importance of sex as a biological variable in exercise‐induced cytokine remodeling and support the utility of TFEB overexpression as a platform for prioritizing exercise‐associated phenotypes.