Exercise induces cardioprotective remodelling in the hearts of aged female and male mice

F. Betge (Zürich)¹, G. Germena (Zürich)¹, J. Kang (Zürich)¹, L. Mathez (Zürich)¹, C. Hess (Heidelberg)², W. Abplanalp (Frankfurt am Main)³, D. John (Frankfurt am Main)³, S.-F. Glaser (Frankfurt am Main)³, J. U. G. Wagner (Frankfurt am Main)³, C. Lerchenmüller (Zürich)^1
1Universität Zürich Lehrstuhl Gendermedizin Zürich, Schweiz; ²Universitätsklinikum Heidelberg Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie Heidelberg, Deutschland; ³Goethe Universität Frankfurt am Main Zentrum für Molekulare Medizin, Institut für Kardiovaskuläre Regeneration Frankfurt am Main, Deutschland

Background:
Ageing is an independent risk factor for cardiovascular disease, whereas exercise can be cardioprotective. Sex differences influence age- and exercise-related cardiac remodelling, yet the underlying molecular mechanisms remain insufficiently characterised. The aim of this study was to identify the pathways influenced by lifelong exercise in the hearts of aged female and male mice.

Methods:
Eight-week-old female and male mice were randomly assigned to either voluntary wheel running or sedentary conditions for 18 months. Cardiac function was assessed by serial echocardiography at baseline, and at 6, 12, and 18 months. At endpoint, hearts were harvested for gravimetric and histological analyses, as well as single-nucleus RNA sequencing to characterise exercise-responsive transcriptional programmes across cardiac cell populations in both sexes.

Results:
While females ran more than males, exercise improved global systolic function in both sexes and delayed the age-related decline in cardiac performance. Males exhibited a stronger hypertrophic response to training, whereas females demonstrated a more pronounced exercise-induced reduction of myocardial fibrosis and cardiac inflammation. Sequencing analysis revealed divergent molecular adaptations between the sexes, with the greatest transcriptional response to exercise observed in cardiomyocytes and fibroblasts. In cardiomyocytes, genes enriched in females were associated with RNA regulatory processes, whereas those differentially regulated in males were linked to extracellular matrix organisation. In fibroblasts, exercise induced genes associated with extracellular matrix organisation in females and with contractile function in males.

Conclusion:
Exercise improves cardiac function and induces distinct remodelling mechanisms at histological and transcriptional levels in the hearts of ageing female and male mice. These findings highlight the importance of sex as a biological variable when developing strategies to harness exercise-mediated cardioprotection.