Reversing skeletal muscle dysfunction, hyperhomocysteinemia, and diabetes with exercise (LB679)

Hyperhomocysteinemia (HHcy) induces vascular remodeling and hypertension through production of ROS, MMP‐9, and diminishing NO production. Homocysteine (Hcy) also tends to shift macrophages towards their M1 “pro‐inflammatory” phenotype and away from the M2 “anti‐inflammatory” state, leading to vascular inflammation and hypertension. However, regular exercise acts as a “multi‐pill”, encompassing anti‐hypertensive, anti‐lipid/cholesterolemic, and blood thinning benefits. It reduces Hcy levels in hypertension and diabetes. To test the hypothesis that exercise mitigates hypertension through reduction of Hcy levels and a phenotypic shift from M1 to M2, wild Type C57, MMP‐9 KO, FVB, CBS ‐/+ (HHcy), and Akita (diabetic) mice with and without 4 weeks of exercise are administered a modified swimming protocol. Indices of vascular function were measured using ultrasonography, laser Doppler and tail cuff blood pressure monitoring. Post‐exercise animals were sacrificed. When compared to normotensive animals (C57, MMP‐9 ‐/‐, FVB), the CBS‐/+ and Akita mice have significantly higher baseline blood pressure and smaller luminal diameter with substantially increased wall/lumen ratio. The resistive index was also higher in CBS‐/+ and Akita as compared to controls. The Akita mice demonstrated a significant decline in mean, systolic, and diastolic blood pressure post exercise. Although in FVB (control for MMP‐9‐/‐) mice, we observed a slight but significant decline in mean and diastolic blood pressure, there was no change in MMP‐9‐/‐ group. Our data suggests that Akita and CBS‐/+ mice elicited hypertension and exercise mitigates hypertension in HHcy and diabetes. Grant Funding Source : NIH RO1HL074185