Impaired Critical Speed in Mice with Sickle Cell Anemia

Abstract

Sickle cell anemia results in impaired cardiorespiratory function and exercise tolerance likely due to a combination of central and peripheral abnormalities stemming from deranged hemoglobin (Hb). A transgenic mouse model of sickle cell anemia has been developed to help elucidate the mechanisms of vascular and organ damage, but a valid and reproducible measurement of exercise capacity and the severity of impaired physical function have yet to be determined in this model. PURPOSE: Therefore, the purpose of this investigation was to measure the speed/duration relationship, known as critical speed (CS), and the anaerobic work capacity (AWC, the finite work capacity available above CS) in healthy wild type mice (WT) and mice expressing human HbSS (BERK). METHODS: Following ethical approval from the institutional animal care and use committee (University of Colorado, Denver), six young-adult female mice (WT, n=3 and BERK, n=3) performed 3-5 constant-speed treadmill tests that resulted in fatigue within the range of 1.5 to 20 min. Time to fatigue vs. treadmill speed were fit to a linear and hyperbolic model. RESULTS: Speed and time to exhaustion for both groups conformed to a hyperbolic relationship (WT: r2 = 0.98 ± 0.01, BERK: r2 = 0.98 ± 0.02, p>0.05) which corresponded to a linear 1/time function (WT: r2 = 0.97 ± 0.02, BERK: r2 = 0.94 ± 0.03, P>0.05). CS was significantly lower in BERK mice when compared to the WT control (WT: 34.8 ± 1.3, BERK: 23.2 ± 1.5 m/min, p<0.05) with no differences between linear and hyperbolic models (p>0.05 for both). Additionally, AWC was significantly higher (WT: 1456.2 ± 237.2, BERK: 2639.2 ± 106.8, P<0.05) in BERK relative to WT. CONCLUSIONS: Exercise tolerance, as measured via CS, was severely reduced in BERK mice when compared to WT. Considering that CS represents the highest sustainable rate of aerobic metabolism and the lower CS in BERK mice, these data suggest that sickle cell disease impacts aerobic capacity which may be due to a disruption in the tight matching between oxygen delivery and utilization within the skeletal muscle. In this regard, these results call for future investigations into the mechanisms by which this disease impacts skeletal muscle vascular and metabolic control so that targeted therapies can be developed and employed. Funding: NIH-NHLBI T32HL007171 NIH- R01HL125642.