The Effect of Dietary Nitrate Supplementation on the Speed-Duration Relationship in Mice with Sickle Cell Disease

Sickle cell disease (SCD) compromises nitric oxide (NO) bioavailability and results in a plethora of cardiopulmonary and skeletal muscle complications causing severe exercise intolerance. It is now widely recognized that dietary nitrate can be reduced to nitrite and, subsequently, NO and impact hemodynamic and metabolic control during exercise. Therefore, the purpose of this investigation was to measure the impact of nitrate supplementation on exercise capacity as measured by the running speed/ exercise duration relationship (critical speed, CS) and the anaerobic work capacity (W′, the finite work capacity available above CS) in mice with SCD. We tested the hypothesis that dietary nitrate supplementation via beetroot juice (BR) would attenuate the exercise intolerance observed in mice with SCD. Ten wild‐type (WT) and 18 Berkley sickle‐cell mice (BERK) received either water (WT: n=10, BERK: n=10) or nitrate‐rich BR (BERK+BR: n=8, nitrate dose 1 mmol/kg/day) for five days). Following the supplementation period, all mice performed 4 constant‐speed treadmill tests that resulted in fatigue within 1.5 to 20 min. Time to fatigue vs. treadmill speed were fit to a hyperbolic model to determine CS. Speed and time to exhaustion for WT, BERK, and BERK+BR conformed to a hyperbolic relationship (WT: r2 = 0.93 ± 0.02, BERK: r2 = 0.97 ± 0.01, BERK+BR: r2= 0.97 ± 0.03, p>0.05). CS was significantly lower in BERK when compared to WT and BERK+BR with no significant difference between WT and BERK+BR (WT: 33.1 ± 1.5, BERK: 24.7 ± 0.7, BERK+BR: 31.9 ± 1.4 m/min, p<0.05). Additionally, the W′ was significantly higher in BERK relative to WT and BERK+BR (WT: 1456.2 ± 237.2, BERK: 2639.2 ± 106.8, BERK+BR: 1134.7 ± 156.7, P<0.05). To summarize, exercise tolerance, as measured via CS, was significantly lower in BERK mice relative to WT. However, BERK mice that had received a 5‐day dietary nitrate intervention exhibited no difference in exercise tolerance when compared to WT. In addition, the W′ was significantly higher in BERK mice relative to WT, but this difference was not observed in BERK+BR. The CS threshold is a well‐described fundamental feature of exercise energetics that represents the highest sustainable rate of aerobic metabolism and remains valid across species. Considering the lower CS in BERK mice and the ability of BR to restore CS in BERK mice, these results provide compelling support for the use of a dietary nitrate intervention to improve functionality in the SCD patient population.Support or Funding InformationFunded by NIH (R01HL125642) to DCI and Colorado Nutrition and Obesity Research Center (P30DK048520) award to SKF.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.