Metabolic correlates to critical speed in murine models of sickle cell disease.
Metabolic correlates to critical speed in murine models of sickle cell disease.
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DOI：
10.3389/fphys.2023.1151268
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发表时间：
2023
影响因子：
4
通讯作者：
中科院分区：
文献类型：
--
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运动不耐受是镰状细胞病（SCD）患者常见的临床表现，但其机制尚不完全清楚。方法：在这里，我们利用小鼠镰状细胞病模型，即伯克利小鼠，通过测定临界速度（CS）来表征对运动的反应，CS是一种功能测量小鼠在努力到疲惫时的跑步速度。结果：在观察到临界速度表型的广泛分布后，我们系统地确定了基于临界速度表现排名的小鼠血浆和器官（包括心脏、肾脏、肝脏、肺和脾脏）的代谢畸变（前25% vs后25%）。结果表明，羧酸、鞘氨醇1-磷酸和酰基肉碱代谢的系统性和器官特异性改变具有明确的特征。这些途径中的代谢物在所有基质中显示出与临界速度显著相关。因此，小鼠模型的发现在433例镰状细胞病（SS基因型）患者中得到了进一步验证。该队列中281名受试者的血浆代谢组学分析（HbA < 10%以减少近期输血事件的混淆效应）用于确定代谢与亚最大运动测试表现的相关性，作为该临床队列中6分钟步行测试的测量。结果证实了测试表现与循环羧酸（特别是琥珀酸）和鞘氨醇1-磷酸水平失调之间的强烈相关性。讨论：我们在镰状细胞病小鼠模型和镰状细胞患者中发现了新的运动不耐受循环代谢标志物。
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.
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