Exercise-responsive transcriptional signatures link T-cell immunometabolic remodeling with cardiovascular and cardiac adaptation in type 2 diabetes

Type 2 diabetes (T2D) is associated with physical inactivity, immune dysregulation, and cardiovascular complications. How exercise-responsive genes relate to T-cell states and tissue responses remains unclear. We assessed associations of physical activity (PA) with T2D, glycemic traits, and cardiovascular outcomes in the National Health and Nutrition Examination Survey (NHANES). Exercise-responsive genes were identified from human and mouse skeletal-muscle transcriptomes and examined in a human peripheral blood mononuclear cell (PBMC) single-cell dataset. Splenic single-cell RNA sequencing and flow cytometry characterized T-cell transcriptional states and phenotypes in exercise-trained db/db mice, while two mouse heart RNA-seq datasets were used to assess cardiac transcriptional responses. Higher PA was associated with lower T2D prevalence and more favorable glycemic profiles, as well as lower cardiovascular mortality among participants with T2D. Exploratory cross-species analysis identified 18 exercise-responsive candidate genes, with JUNB expression varying along inferred T-cell pseudotime. Compared with healthy controls, PBMC T cells from patients with periodontitis and diabetes mellitus (PDDM) had lower TrainingScores, higher transcriptome-based phenylalanine-metabolism scores, and altered inferred THBS1-CD47 communication. In db/db mice, splenic single-cell analysis identified eight T-cell states and a higher pooled-cell mean exercise-response score in regulatory T cells (Tregs) after exercise, while flow cytometry showed higher Foxp3 + CD4+ Treg proportions and lower pro-inflammatory CD4 + T-cell fractions. Heart RNA-seq revealed partially concordant pathway-level responses across the two datasets. Exercise-responsive candidates exhibited tissue- and cell-state-dependent expression patterns, and exercise-trained db/db mice showed changes in T-cell proportions and cardiac transcriptional and morphological features. These findings support JUNB as a candidate for further mechanistic investigation.