Physical Activity-Related Metabolites Are Associated with Mortality: Findings from the Atherosclerosis Risk in Communities (ARIC) Study

Abstract

Habitual physical activity can diminish the risk of premature death. Identifying a pattern of metabolites related to physical activity may advance our understanding of disease etiology. We quantified 245 serum metabolites in 3802 participants from the Atherosclerosis Risk in Communities (ARIC) study using chromatography–mass spectrometry. We regressed self-reported moderate-to-vigorous intensity leisure-time physical activity (LTPA) against each metabolite, adjusting for traditional risk factors. A standardized metabolite risk score (MRS) was constructed to examine its association with all-cause mortality using the Cox proportional hazard model. We identified 10 metabolites associated with LTPA (p < 2.04 × 10−4) and established that an increase of one unit of the metabolic equivalent of task-hours per week (MET·hr·wk−1) in LTPA was associated with a 0.012 SD increase in MRS. During a median of 27.5 years of follow-up, we observed 1928 deaths. One SD increase of MRS was associated with a 10% lower risk of death (HR = 0.90, 95% CI: 0.85–0.95). The highest vs. the lowest MRS quintile rank was associated with a 22% reduced risk of death (HR = 0.78, 95% CI: 0.62–0.94). The effects were consistent across race and sex groups. In summary, we identified a set of metabolites associated with LTPA and an MRS associated with a lower risk of death. Our study provides novel insights into the potential mechanisms underlying the health impacts of physical activity.

Metabolomic profiles associated with physical activity in White and African American adult men

“…A deficiency of human glycerate kinase leads to D-glycerate acidemia/D-glyceric aciduria. Our findings are consistent with a previous study that reported moderate-to-vigorous-intensity leisure-time PA is positively related to glycerate in both AAs and Whites in the respective and pooled samples [41]. Our findings suggest that PA may increase glycerate concentration, and the influence was dependent on regular PA frequency.…”

Metabolomic Signatures of Sedentary Behavior and Cardiometabolic Traits in US Hispanics/Latinos: Results from HCHS/SOL

“…Using a weighted correlation network analysis on 102 metabolites, 8 distinct sedentary metabolite modules on 56 highly connected metabolites were identified, excluding 46 metabolites with low overall connectivity (Fig. 2, the average of module size was 7 metabolites composing a module; range, [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. We named the modules, by the most frequently represented pathways in the module, as BCAA, erythritol, PUFA, creatine, urea cycle, plasmalogen glycerol phosphatidyl ethanolamine (GPE)-ethanolamine plasmalogen subclass, plasmalogen GPC, and acyl choline.…”

“…There are several epidemiological studies examining the metabolomic shifts by habitual physical activity (6)(7)(8)(9)(10)(11)(12), but only a few studies addressing sedentary time (8)(9)(10). Consistent with cellular and physiological mechanisms of physical activity (4), metabolomic profiling supports (13) that physical activity may activate the catabolism of branched-chain amino acids (BCAA) linked with increased mitochondrial fatty acid oxidation (low BCAA and its derivative 4-methyl-2-oxopentanoate) (6,8,9), glucose homeostasis (low glucose, alanine, proline, and lactate) (6,(8)(9)(10), and anti-inflammatory pathway (low glycoprotein acetyls) (10).…”