Exercise (In)Tolerance in Sickle Cell Disease: Potential Disruptive Role of Free Hemoglobin on Skeletal Muscle Oxygen Delivery/Utilization Matching and Functional Capacity

Sickle cell disease (SCD) reduces exercise tolerance likely due to vascular and skeletal muscle abnormalities stemming from increased free hemoglobin (Hb, a known scavenger of nitric oxide). However, there has been little advancement in our understanding of the precise mechanisms responsible for the reduction in physical functionality. Therefore, the purpose of this investigation was 1) determine the degree by which exercise tolerance is impaired in a mouse model of SCD (BERK) and 2) examine the impact of free Hb on the skeletal muscle microvascular PO 2 (PO 2 mv, the principal driving force that facilitates blood‐muscle O 2 flux) at rest and during muscle contractions in rats exposed to acutely elevated free [Hb]. We hypothesized that exercise capacity, as measured by the running speed/exercise duration relationship (critical speed, CS), would be lower in BERK relative to wild‐type mice (WT) with a lower PO 2 mv observed during muscle contractions following Hb infusion. Twenty female mice (WT, n=10 and BERK, n=10) 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. PO 2 mv was measured (phosphorescence quenching) at rest and during 180 s of electrically induced (1‐Hz) spinotrapezius muscle contractions during control, following free Hb infusion (Hb, 50 mg), and L‐nitro arginine methyl ester superfusion (L‐NAME, 1.5 mM) conditions in 9 rats. Speed and time to exhaustion for WT and BERK conformed to a hyperbolic relationship (WT: r 2 = 0.93 ± 0.02, BERK: r 2 = 0.97 ± 0.01, p>0.05). CS was significantly lower in BERK when compared to WT (WT: 33.1 ± 1.5, BERK: 25.2 ± 0.7 m/min, p<0.05). Following the onset of muscle contractions, Hb and L‐NAME significantly increased the amplitude of the fall in PO 2 mv when compared to control, with no significant differences between Hb and L‐NAME conditions (Δ1PO 2 mv: control: 9.5±0.7, Hb: 11.7±1, L‐NAME 10.4±0.8 mmHg, p<0.05). The increased Δ1PO 2 mv resulted in a significantly lower PO 2 mv during the steady‐state of muscle contractions in both Hb and L‐NAME conditions, with no differences between Hb and L‐NAME (PO 2 mv (steady‐state) : control: 24.1±0.9, Hb: 21.3±0.7, L‐NAME: 19.6±1 mmHg, p<0.05). To summarize, exercise tolerance, as measured via CS, was significantly lower in BERK mice relative to WT. Furthermore, the lower PO 2 mv (steady‐state) in Hb and L‐NAME represents a compromised blood‐myocyte O 2 driving force during muscle contractions. Collectively, these data suggest that SCD impacts physical capacity via a disruption in the tight matching between oxygen delivery and utilization within the skeletal muscle and that this dysfunction could be mediated by a reduced nitric oxide bioavailability consequent of elevated free [Hb]. Support or Funding Information Funded by NIH (R01HL125642) to DCI and Colorado Nutrition and Obesity Research Center (P30DK048520) award to SKF.Mean percent PO 2 mv for the spinotrapezius muscle for control, Hb, and L‐NAME conditions. Time “zero” represents the onset of electrically stimulated 1‐hz twitch muscle contractions.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .