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

Autor:	Cendali FI; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO, United States., Nemkov T; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO, United States., Lisk C; Department of Pulmonology, University of Colorado Denver, Aurora, CO, United States., Lacroix IS; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO, United States., Nouraie SM; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Zhang Y; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Gordeuk VR; Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States., Buehler PW; Department of Pathology, University of Maryland, Baltimore, MD, United States.; Center for Blood Oxygen Transport, Department of Pediatrics, Baltimore, MD, United States., Irwin D; Department of Pulmonology, University of Colorado Denver, Aurora, CO, United States., D'Alessandro A; Department of Pulmonology, University of Colorado Denver, Aurora, CO, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in physiology [Front Physiol] 2023 Mar 13; Vol. 14, pp. 1151268. Date of Electronic Publication: 2023 Mar 13 (Print Publication: 2023).
DOI:	10.3389/fphys.2023.1151268
Abstrakt:	Introduction: Exercise intolerance is a common clinical manifestation in patients with sickle cell disease (SCD), though the mechanisms are incompletely understood. Methods: Here we leverage a murine mouse model of sickle cell disease, the Berkeley mouse, to characterize response to exercise via determination of critical speed (CS), a functional measurement of mouse running speed upon exerting to exhaustion. Results: Upon observing a wide distribution in critical speed phenotypes, we systematically determined metabolic aberrations in plasma and organs-including heart, kidney, liver, lung, and spleen-from mice ranked based on critical speed performances (top vs. bottom 25%). Results indicated clear signatures of systemic and organ-specific alterations in carboxylic acids, sphingosine 1-phosphate and acylcarnitine metabolism. Metabolites in these pathways showed significant correlations with critical speed across all matrices. Findings from murine models were thus further validated in 433 sickle cell disease patients (SS genotype). Metabolomics analyses of plasma from 281 subjects in this cohort (with HbA < 10% to decrease confounding effects of recent transfusion events) were used to identify metabolic correlates to sub-maximal exercise test performances, as measure by 6 min walking test in this clinical cohort. Results confirmed strong correlation between test performances and dysregulated levels of circulating carboxylic acids (especially succinate) and sphingosine 1-phosphate. Discussion: We identified novel circulating metabolic markers of exercise intolerance in mouse models of sickle cell disease and sickle cell patients. Competing Interests: The authors declare that AD’A and TN are founders of Omix Technologies Inc. AD’A is an advisory board member of Macopharma and Hemanext Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Cendali, Nemkov, Lisk, Lacroix, Nouraie, Zhang, Gordeuk, Buehler, Irwin and D’Alessandro.)
Databáze:	MEDLINE
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