Hypercholesterolemia impairs exercise capacity in mice.
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.
Maxwell
Andrew J
AJ
Division of Cardiovascular Medicine, Program in Vascular Medicine and Biology, Stanford University, Stanford, CA 94305-5246, USA.
Niebauer
Josef
J
Lin
Patrick S
PS
Tsao
Philip S
PS
Bernstein
Daniel
D
Cooke
John P
JP
D000375:Aging; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002791:Cholesterol, Dietary / Q000097:blood; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004195:Disease Models, Animal; D017079:Exercise Tolerance; D005260:Female; D006937:Hypercholesterolemia / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000473:pathology; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000378:metabolism; D014664:Vasodilation
D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D009566:Nitrates; D009569:Nitric Oxide; D002950:Citrate (si)-Synthase