Cardiology Division and the Simches Cardiovascular Research Center, Department of Medicine, Harvard Medical School (M.N., R.V.S., J.B.B., M.T., R.M., N.E.H., J.E.H., A.L.B., G.D.L.), Massachusetts General Hospital, Boston.
Department of Biostatistics, Boston University School of Public Health, MA (P.E.M., M.G.L.).
Circulation. 2020 Nov 17;142(20):1905-1924. doi: 10.1161/CIRCULATIONAHA.120.050281. Epub 2020 Sep 15.
Whereas regular exercise is associated with lower risk of cardiovascular disease and mortality, mechanisms of exercise-mediated health benefits remain less clear. We used metabolite profiling before and after acute exercise to delineate the metabolic architecture of exercise response patterns in humans.
Cardiopulmonary exercise testing and metabolite profiling was performed on Framingham Heart Study participants (age 53±8 years, 63% women) with blood drawn at rest (n=471) and at peak exercise (n=411).
We observed changes in circulating levels for 502 of 588 measured metabolites from rest to peak exercise (exercise duration 11.9±2.1 minutes) at a 5% false discovery rate. Changes included reductions in metabolites implicated in insulin resistance (glutamate, -29%; =1.5×10; dimethylguanidino valeric acid [DMGV], -18%; =5.8×10) and increases in metabolites associated with lipolysis (1-methylnicotinamide, +33%; =6.1×10), nitric oxide bioavailability (arginine/ornithine + citrulline, +29%; =2.8×10), and adipose browning (12,13-dihydroxy-9Z-octadecenoic acid +26%; =7.4×10), among other pathways relevant to cardiometabolic risk. We assayed 177 metabolites in a separate Framingham Heart Study replication sample (n=783, age 54±8 years, 51% women) and observed concordant changes in 164 metabolites (92.6%) at 5% false discovery rate. Exercise-induced metabolite changes were variably related to the amount of exercise performed (peak workload), sex, and body mass index. There was attenuation of favorable excursions in some metabolites in individuals with higher body mass index and greater excursions in select cardioprotective metabolites in women despite less exercise performed. Distinct preexercise metabolite levels were associated with different physiologic dimensions of fitness (eg, ventilatory efficiency, exercise blood pressure, peak Vo). We identified 4 metabolite signatures of exercise response patterns that were then analyzed in a separate cohort (Framingham Offspring Study; n=2045, age 55±10 years, 51% women), 2 of which were associated with overall mortality over median follow-up of 23.1 years (≤0.003 for both).
In a large sample of community-dwelling individuals, acute exercise elicits widespread changes in the circulating metabolome. Metabolic changes identify pathways central to cardiometabolic health, cardiovascular disease, and long-term outcome. These findings provide a detailed map of the metabolic response to acute exercise in humans and identify potential mechanisms responsible for the beneficial cardiometabolic effects of exercise for future study.
尽管有规律的运动与降低心血管疾病和死亡率的风险有关，但运动介导的健康益处的机制仍不明确。我们使用代谢组学方法在急性运动前后对 Framingham 心脏研究参与者（年龄 53±8 岁，63%为女性）进行了心肺运动测试和代谢组学分析，采集了运动前（n=471）和运动峰值时（n=411）的血液样本。
在 Framingham 心脏研究参与者（年龄 53±8 岁，63%为女性）中进行心肺运动测试和代谢组学分析，采集运动前（n=471）和运动峰值时（n=411）的血液样本。
在经过 5%假发现率（FDR）筛选后，我们观察到 588 种测量代谢物中有 502 种在静息状态到运动峰值（运动持续时间 11.9±2.1 分钟）之间的循环水平发生了变化。这些变化包括与胰岛素抵抗相关的代谢物水平降低（谷氨酸，-29%； =1.5×10；二甲基胍基戊酸[DMGV]，-18%； =5.8×10）和与脂肪分解相关的代谢物水平升高（1-甲基烟酰胺，+33%； =6.1×10），与一氧化氮生物利用度相关的代谢物水平升高（精氨酸/鸟氨酸+瓜氨酸，+29%； =2.8×10），以及与脂肪棕色化相关的代谢物水平升高（12,13-二羟基-9Z-十八烯酸，+26%； =7.4×10），以及其他与心血管代谢风险相关的途径。我们在一个独立的 Framingham 心脏研究复制样本（n=783，年龄 54±8 岁，51%为女性）中检测了 177 种代谢物，并在经过 5% FDR 筛选后观察到 164 种代谢物（92.6%）发生了一致性变化。运动诱导的代谢物变化与运动强度（最大负荷）、性别和体重指数等因素有关。在体重指数较高的个体中，一些代谢物的有益变化幅度减弱，而在女性中，一些特定的心脏保护代谢物的变化幅度增大，尽管运动强度较低。不同的运动前代谢物水平与不同的身体适应能力维度相关（如通气效率、运动血压、最大摄氧量）。我们确定了 4 种与运动反应模式相关的代谢物特征，然后在一个独立的队列（Framingham 后代研究；n=2045，年龄 55±10 岁，51%为女性）中进行了分析，其中 2 种与中位随访 23.1 年的全因死亡率相关（均<0.003）。
在一个大型的社区居住个体样本中，急性运动引起了循环代谢组的广泛变化。代谢变化确定了与心血管代谢健康、心血管疾病和长期预后相关的核心途径。这些发现为人类急性运动对代谢的反应提供了详细的图谱，并确定了潜在的机制，为未来研究运动的有益心血管代谢效应提供了线索。
