Effects of short-term moderate intensity exercise on the serum metabolome in older adults: a pilot randomized controlled trial

Abstract

Background: We previously reported changes in the serum metabolome associated with impaired myocardial relaxation in an asymptomatic older community cohort. In this prospective parallel-group randomized control pilot trial, we subjected community adults without cardiovascular disease to exercise intervention and evaluated the effects on serum metabolomics.

Methods: Between February 2019 to November 2019, thirty (83% females) middle-aged adults (53 ± 4 years) were randomized with sex stratification to either twelve weeks of moderate-intensity exercise training (Intervention) (n = 15) or Control (n = 15). The Intervention group underwent once-weekly aerobic and strength training sessions for 60 min each in a dedicated cardiac exercise laboratory for twelve weeks (ClinicalTrials.gov: NCT03617653). Serial measurements were taken pre- and post-intervention, including serum sampling for metabolomic analyses.

Results: Twenty-nine adults completed the study (Intervention n = 14; Control n = 15). Long-chain acylcarnitine C20:2-OH/C18:2-DC was reduced in the Intervention group by a magnitude of 0.714 but increased in the Control group by a magnitude of 1.742 (mean difference -1.028 age-adjusted p = 0.004). Among Controls, alanine correlated with left ventricular mass index (r = 0.529, age-adjusted p = 0.018) while aspartate correlated with Lateral e' (r = -764, age-adjusted p = 0.016). C20:3 correlated with E/e' ratio fold-change in the Intervention group (r = -0.653, age-adjusted p = 0.004). Among Controls, C20:2/C18:2 (r = 0.795, age-adjusted p = 0.005) and C20:2-OH/C18:2-DC fold-change (r = 0.742, age-adjusted p = 0.030) correlated with change in E/A ratio.

Conclusions: Corresponding relationships between serum metabolites and cardiac function in response to exercise intervention provided pilot observations. Future investigations into cellular fuel oxidation or central carbon metabolism pathways that jointly impact the heart and related metabolic systems may be critical in preventive trials.

Fig. 1

The EaRneST trial CONSORT flow diagram. Thirty community adults from the Cardiac Aging Study had volunteered to participate in this exercise trial between February 2019 and November 2019 and were randomized by sex-stratification equally into Intervention (Exercise) and Control groups. Within the Intervention group, one participant was excluded after an abnormal exercise treadmill test, while the remaining 14 participants completed the exercise intervention. In total, 29 participants were analysed at the study completion.

Fig. 2. Effect of intervention on metabolomic markers.

Box-and-whisker plots of fold-change in serum metabolomics after the exercise period in the Intervention (n = 14) and Control (n = 15) groups. The horizontal lines represent quartiles, while the cross (denoted “X”) represents the mean value. The error bars represent the range from the minimum and maximum values. Mann Whitney U tests were used for comparisons. P-values are two-tailed. In the Intervention group, there were significant relative increases in serum amino acids alanine (p = 0.029) and arginine (p = 0.046), as well as C12:2-OH/C10:2-DC (p = 0.033) compared to Controls, whilst C20:2-OH/C18:2-DC decreased (p < 0.001). Ala indicates alanine, Arg Arginine.

Fig. 3. Effect of intervention on diastolic function and vascular stiffness.

Box-and-whisker plots before and after exercise intervention. The horizontal lines represent quartiles, while the cross (denoted “X”) represents the mean value. The error bars represent the range from the minimum and maximum value. A, B Changes in echocardiographic parameters and pulse wave velocity after the exercise period in the Intervention group (n = 14). C, D Changes in echocardiographic parameters and pulse wave velocity in the Control group (n = 15). The units for Lateral e’ are reported here in cm/second to fit the y-axis of the other variables. Error bars represent quartiles with the mean marked “X”. Mann Whitney U tests were used for comparisons. P-values are two-tailed. In the Control group, Lateral e' decreased (p = 0.033), and pulse wave velocity increased (p = 0.059). The Intervention group remained unchanged. Mitral A wave indicates mitral inflow peak velocity in late diastole; E wave, early diastolic mitral inflow peak velocity; lateral e’, lateral mitral annular peak velocity in early diastolic; E/e’, ratio of mitral E wave to the average e’.

Fig. 4. Correlations between serum long-chain acylcarnitines with E/A ratio.

A, B Change in C20:2/C18:2 plotted against change in E/A ratio (A) and fold-change in E/A ratio (B). C, D Fold-change in C20:2-OH/C18:2-DC plotted against E/A ratio (C) and fold-change in E/A ratio (D). Spearman’s rank-order correlation was used to assess the relationships between metabolites and cardiac function. Adjustments for age were made using multiple regression. In the Intervention group (n = 14), inverse correlations between C20:2/C18:2 and E/A ratio (A, R = −0.535, p = 0.049, adj. p = 0.078) and E/A fold-change (B, R = −0.486, p = 0.078, adj. p = 0.084) were not significant; while in the Control group (n = 15), E/A ratio and E/A fold-change were both positively correlated (A, R = 0.795, p < 0.001, adj. p = 0.005; B, R = 0.789, p < 0.001, adj. p = 0.003 respectively). Comparing C20:2-OH/C18:2-DC, E/A ratio and E/A fold-change both trended towards an inverse correlation in the Intervention group (C, R = −0.361, age-adjusted p = 0.160; D, R = −0.358, adj. p = 0.159, respectively) while both having a positive correlation in the Control group (C, R = 0.742 age-adjusted p = 0.030; D, R = 0.736 adj. p = 0.017, respectively). E/A ratio indicates ratio of early to late peak diastolic mitral inflow velocity.

Fig. 5. Correlations between Lateral e’, E/e' ratio, LVMI and serum metabolites.

A change in C20:3 plotted against fold-change in E/e' ratio. B Change aspartate plotted against Lateral e’. C, D Change in a serum long-chain acylcarnitine C18 and alanine plotted against LVMI, respectively. Spearman’s correlation was used to assess the relationships between metabolites and cardiac function. Adjustments for age were made using multiple regression. A C20:3 was inversely correlated with E/e' ratio fold-change in the Intervention group (n = 14) (R = −0.653, p = 0.011, adj. p = 0.004) but not the Control group (n = 15) (R = −0.121, adj. p = 0.351). B Aspartate was not correlated with Lateral e' in the Intervention group (R = −0.311 adj. p = 0.477) but was negatively correlated in the Control group (R = −764, p = 0.001, adj. p = 0.016). C, D C18 and alanine were not correlated with LVMI in the Intervention group (C, R = −0.143, adj. p = 0.674; D, R = −0.029, adj. p = 0.874, respectively) but were positively correlated in the Control group (C, R = −0.614 p = 0.015, adj. p = 0.012; D R = 0.529, p = 0.043, adj. p = 0.018, respectively). Ala indicates Alanine; Asp, Aspartate; E/e’ ratio, ratio of early diastolic mitral inflow peak velocity (E) to lateral mitral annulus early diastolic peak velocity (e’); Lateral e’, lateral mitral annulus early diastolic peak velocity; LVMI left ventricular mass index.