We previously reported an attenuation of both exercise
hyperemia and measures of aerobic capacity in hypercholesterolemic mice. In this study, we expanded upon the previous findings by examining the temporal and quantitative relationship of
hypercholesterolemia to aerobic and anaerobic capacity and by exploring several potential mechanisms of dysfunction. Eight-week-old wild type (n = 123) and
apoE knockout (n = 79) C57BL/6J mice were divided into groups with distinct
cholesterol levels by feeding with regular or high-fat diets. At various ages, the mice underwent treadmill ergospirometry. To explore mechanisms, aortic ring
vasodilator function and
nitrate (NO(x)) activity, urinary excretion of NO(x), running muscle microvascular density and
citrate synthase activity, as well as myocardial mass and histologic evidence of
ischemia were measured. At 8 weeks of age, all mice had similar measures of exercise capacity. All indices of aerobic exercise capacity progressively declined at 12 and 20 weeks of age in the hypercholesterolemic mice as
cholesterol levels increased while indices of anaerobic capacity remained unaffected. Across the four
cholesterol groups, the degree of aerobic dysfunction was related to serum
cholesterol levels; a relationship that was maintained after correcting for confounding factors. Associated with the deterioration in exercise capacity was a decline in measures of
nitric oxide-mediated vascular function while there was no evidence of aberrations in functional or oxidative capacities or in other components of transport capacity. In conclusion, aerobic exercise dysfunction is observed in murine models of genetic and diet-induced
hypercholesterolemia and is associated with a reduction in vascular
nitric oxide production.