Beneficial effects of exercise training on expression of fibrosis-related genes in a mouse model of hypertrophic cardiomyopathy. (10th June 2022) - Andreassen, K
Abstract: Funding Acknowledgements: Type of funding sources: Public Institution(s). Main funding source(s): South-Eastern Norway Regional Health Authority (HSØ) KG Jebsen Cardiac Research Center Background: The effects of exercise training prior to manifestation of phenotype in hypertrophic cardiomyopathy (HCM) are unknown. In mice carrying the HCM-pathogenic α-MHC R403Q/+ (R403Q) genetic variant, accelerated progression of the HCM phenotype is induced by cyclosporine A (CsA). We used this model to determine if exercise training initiated before phenotype development could limit disease severity. Methods: R403Q mice were allocated to treadmill exercise training (N=23) or sedentary behavior (N=23) for 6 weeks. For the last three weeks of the 6-week period, all mice received CsA to induce the HCM phenotype. Cardiac imaging (echocardiography or MRI) and exercise testing were performed at the 0, 3 and 6-week time points. After the 6-week exercise protocol, left ventricles were harvested for molecular analyses. Results: After 6 weeks, exercise trained mice ran 2-fold further during testing than sedentary mice (p<0.0001), and 2-fold further than at baseline (p<0.0001). There was no difference in VO2 max between groups. Cardiac imaging did not reveal differences in hypertrophy between exercised and sedentary HCM mice. However, we observed a reduction in cardiac expression of key fibrosis-related genes in the exercise group, i.e. Col1a2 to 49 % (p=0.03), Col1a1 to 50 % (p=0.03), Col3a1 to 46 % (p=0.02), Fn1 to 49 % (p=0.01) and Lox to 58 % (p=0.05) of levels in the sedentary group. HPLC did not reveal differences in collagen protein. Conclusion: Exercise training initiated prior to manifestation of the HCM phenotype in mice results in lowered production of key fibrosis-related genes, including structural collagens. Further analysis is needed to determine the functional consequences of these beneficial changes in gene expression.