Abstract Body: Background: We previously showed that cardiac-specific expression of constitutively active Nrf2 (caNrf2-TG) induces reductive stress (RS), leading to pathological cardiac remodeling and diastolic dysfunction. Here, we hypothesized that moderate exercise could improve cardiac function and mitigate RS-induced maladaptive remodeling in caNrf2-TG mice.
Methods: TG exercise mice (TG-EXE; n=6) began treadmill training after a 2-week acclimatization at 4 weeks of age and exercised at a 5° incline (15 m/min, 45 min/day, 6 days/week) from 6 to 24 weeks. Age-matched sedentary TG (TG-SED) and non-transgenic (NTG) controls were maintained under identical conditions. Pre- and post-intervention echocardiography were performed and mice were euthanized at 24 weeks of age.
Results: Global longitudinal strain (GLS) analysis demonstrated a significant improvement in left ventricular contractile function in TG mice following exercise compared with sedentary TG mice (TG-EXE vs TG-SED, P<0.0001). Increased ejection fraction observed was normalized after exercise in TG mice. Although cardiac output was increased in TG-SED mice compared with NTG controls, exercise further enhanced cardiac output in TG mice. Diastolic dysfunction observed in TG-SED mice was restored toward normal in TG-EXE animals in the apical four-chamber view. Exercise shortened IVCT (24.8 ± 1.9 vs 18.6 ± 1.5 ms, P<0.05) and IVRT (27.9 ± 2.1 vs 20.4 ± 1.7 ms, P<0.01), while restoring ET toward normal values (42.3 ± 2.8 vs 50.1 ± 3.0 ms, P<0.05), resulting in a reduced MPI (0.62 ± 0.05 vs 0.39 ± 0.04, P<0.01). Strain analysis showed increased peak systolic longitudinal strain rate (-3.1 ± 0.3 vs -4.6 ± 0.4/s, P<0.01) and early diastolic longitudinal strain rate (3.4 ± 0.4 vs 5.2 ± 0.5/s, P<0.01), indicating improved contractile and relaxation kinetics. Exercise did not significantly alter cardiac functional or strain parameters in NTG mice.
Conclusion: Moderate treadmill exercise alleviates reductive stress–induced cardiac dysfunction and improves systolic and diastolic performance, suggesting a potential non-pharmacological strategy to counteract RS-mediated cardiomyopathy.