The effect of dietary nitrate supplementation on the speed-duration relationship in mice with sickle cell disease

Abstract

Sickle cell disease (SCD) causes exercise intolerance likely due to impaired skeletal muscle function and low nitric oxide (NO) bioavailability. Dietary nitrate improves hemodynamic and metabolic control during exercise in humans and animals. The purpose of this investigation was to assess the impact of nitrate supplementation on exercise capacity as measured by the running speed to exercise duration relationship (critical speed (CS)) in mice with SCD. We tested the hypothesis that 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 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 3-5 constant-speed treadmill tests that resulted in exhaustion within 1.5 to 20 min. Time to exhaustion vs. treadmill speed was fit to a hyperbolic model to determine CS. CS was significantly lower in BERK vs. WT and BERK+BR with no significant difference between WT and BERK+BR (WT: 36.6 ± 1.6, BERK: 23.8 ± 1.5, BERK+BR: 31.1 ± 2.1 m/min, p<0.05). Exercise tolerance, measured via CS, was significantly lower in BERK mice relative to WT. However, BERK mice receiving 5 days of nitrate supplementation exhibited no difference in exercise tolerance when compared to WT. These results support the potential utility of a dietary nitrate intervention to improve functionality in SCD patients.

Effects of beetroot juice supplementation on vascular functional and structural changes in aged mice

“…Some evidence suggests that BRJ supplementation increases NO levels in mice (Ferguson et al, 2020 ; Tropea et al, 2020 ). In this study, BRJ supplementation enhanced plasma nitrate levels in aged mice.…”

Metabolic correlates to critical speed in murine models of sickle cell disease

“…Following successful completion of the constant speed treadmill tests, the CS and finite distance capacity (D′) were calculated for each mouse using the linear 1/time model (Speed = D' × 1/time + CS) as described previously ( Ferguson et al, 2019 ; Ferguson et al, 2020 ; Buehler et al, 2021a ). In this model, the treadmill speed used for the constant speed test is plotted as a function of the inverse of time to exhaustion and the y -intercept of the regression line yields the CS and the slope is the D'.…”

Effects of hydroxyurea on skeletal muscle energetics and force production in a sickle cell disease murine model

“…The authors attributed these improvements to hematological (e.g., increased fetal Hb level and decreased HbS level), hemorheological (e.g., increased red blood cell deformability) and hemodynamical (e.g., increased circulating NO level) benefits associated with HU treatment (68). It is interesting to note that a supplementation in nitrate, a NO precursor, has been reported to enhance local blood flow but also muscle function, including in SCD (69)(70)(71)(72). This is especially interesting taking into account that i) NO bioavailability is reduced in SCD patients (4) and ii) that HU can act like nitrate supplementation by promoting NO production (73).…”