AGE AND SEX-DEPENDENT EFFECTS OF DIETARY NITRATES WITH AND WITHOUT EXERCISE ON FRAILTY AND CARDIAC HEALTH IN C57BL/6 MICE.

Abstract

Nitrate supplements are commonly combined with aerobic exercise to potentially improve both performance and cardiac function, but research has mostly used young male participants. Hence, whether this combination improves cardiac function in females or improves age-related cardiovascular deterioration is unclear. It is also unknown whether the combination of exercise and nitrates improves frailty in young or old mice. This study provided young (7-9 mos) and old (24 mos) male and female mice 1 mM sodium nitrate in drinking water, access to a voluntary running wheel, both, or neither for 12 weeks. Health was measured using a frailty index, body composition scan (DEXA), and treadmill fitness test at baseline and endpoint. Cardiac health was assessed in young and old mice using echocardiography, myocardial strain, electrocardiography, blood pressure, and renal blood flow at baseline, midpoint and endpoint. At endpoint ventricular cardiomyocytes were paced at 2 Hz and loaded with Fura-2 dye to measure contractions and calcium transients. Expression levels of calcium handling proteins were measured in ventricular tissue. In young mice both exercise and nitrates prevented detrimental changes in body composition but only the combination of exercise and nitrates improved frailty and increased exercise volume in females. Nitrates alone protected older female mice against detrimental increases in frailty and improved older male body composition while the combination of exercise and nitrates had little effect. Cardiovascular effects were also assessed in young mice. Exercise was beneficial for cardiac structure and function for mostly female mice. While nitrates improved blood pressure, they reduced systolic function in young male mice. The combination intervention abolished most of the beneficial cardiac effects of exercise in female mice. This occurred as nitrates plus exercise negatively impacted calcium handling in young females. In older mice, nitrates improved blood pressure but also decreased systolic function in older female mice. However, in older males the beneficial effects of exercise were largest in nitrate supplemented mice. In conclusion, there were sex and age specific effects of the combination of aerobic exercise and sodium nitrate where the combination was most beneficial in older male mice and detrimental in young female mice.