Forced Exercise Prevents Reductive Stress Induced Cardiomyocyte Remodeling And Cardiac Dysfunction

Background: Disruption of the endoplasmic reticulum (ER) function has been recognizedas a clinical signature of congestive heart failure, ischemia, and atherosclerosis. Whilepro-oxidative redox milieu is vital for the ER to regulate protein folding events. Recently,we reported that overabundant antioxidants in the heart cause reductive stress (RS) andimpair the protein folding mechanisms due to unresolved ER stress. Here, we testedwhether forced exercise prevents RS and improves ER function through augmenting ROSsignaling, thereby improving the PQC mechanisms in the heart. Methods: Cardiac-specific constitutively active Nrf2 (CaNrf2-TG) and non-transgenic (NTG) mice at 5-6weeks of age were subjected to forced treadmill exercise (FTE) for 20 weeks (15meters/minute with a 5° slope; for 45 minutes/day; for 6 days every week). Cardiacstructure and function were analyzed before and after the exercise. At 22 weeks, micewere sacrificed for analysis to assess the benefits of FTE. Results: RNA sequencingrevealed significant downregulation of key protein folding genes and chaperones in TGmice in association with the pathological remodeling at 6 months. Particularly, Pdi, Atf6, Calr, and Ero1α were downregulated (>2 fold) at 24 weeks in TG mice, indicating impairedER function in the remodeling hearts. These changes were coupled with increasedcardiomyocyte size and hypertrophy. Upon FTE, we observed significant improvementsin the structure and function of the cardiomyocytes. WGA staining showed the cross-section area of the cardiomyocytes was significantly reduced in the exercise groupcompared to the sedentary-TG mice experiencing cellular hypertrophy (115.7μm 2 NTGvs 428.8μm 2 TG vs 202.5 μm 2 TG-FTE). Echocardiography analysis demonstratedpreservation of cardiac structure and function (EF, FS, IVD, IVS, EDV, and ESV).Specifically, compensatory improvement in diastolic function (MVE/A ratio) was observedin TG-FTE exe group. Additionally, we observed that the ubiquitination of proteins wassignificantly reduced in the exercise group indicating deaccumulation of the misfoldedproteins in RS hearts. Conclusion: Together these results demonstrate that chronicexercise could ameliorate RS-induced ER stress and cardiac dysfunction.