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

Abstract

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.

Functional and multi-omics signatures of mitapivat efficacy upon activation of pyruvate kinase in red blood cells from patients with sickle cell disease

“… 39 Succinate levels are a predictor of cardiovascular function and exercise intolerance both in murine models and patients with SCD. 26 Here it is interesting to observe that early decreases of proteins of potential mitochondrial origin in the mature erythrocytes were associated with transient elevations and then decreases of carboxylic acids such as succinate. In this regard, we and others previously associated elevation of carboxylic acids, as well as kynurenine levels to activation of cGAS-STING-interferon signaling not just upon viral infection, but also upon age- or disease-related elevations of circulating mitochondrial DNA and RNA.…”