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Acute Exercise Dramatically Changes Metabolite Levels in Middle-aged Adults

Key findings

  • To explore how exercise influences cardiometabolic health, levels of 588 circulating metabolites were measured before and immediately after maximum effort cycle exercise testing in 471 members of the Framingham Heart Study Third Generation
  • Levels of 85% of 588 metabolites changed with exercise, with beneficial alterations observed for metabolites representing key metabolic pathways central to obesity, insulin resistance, oxidative stress, inflammation, vascular reactivity and longevity
  • Distinct metabolite signatures were observed for different physiologic exercise responses such as peak oxygen uptake (reflecting global metabolism), blood pressure response to exercise (reflecting vascular health) and ventilatory efficiency (reflecting central cardiac performance and pulmonary vascular function)
  • Changes in metabolite levels varied by body mass index and sex but were less affected by age
  • Metabolite signatures of physiologic responses to exercise predicted mortality and risk of future cardiovascular disease in 2,045 members of Framingham Heart Study Second Generation over a median of 23 years of follow-up

How exercise benefits cardiovascular, metabolic and general health is still unclear. Matthew Nayor, MD, MPHRavi V. Shah, MD, cardiologists in the Heart Failure and Transplantation Program, and Gregory D. Lewis, MD, cardiologist in the Heart Failure and Transplantation Program at the Corrigan Minehan Heart Center at Massachusetts General Hospital, and colleagues have profiled circulating metabolites in hundreds of people before and after cardiopulmonary exercise testing.

In Circulation, the researchers report that exercise produced widespread metabolic changes in pathways central to cardiometabolic health. Furthermore, these pathways were linked with the long-term risk of cardiovascular disease and death.

Study Details

The authors studied members of the Framingham Heart Study—Third Generation cohort who participated in maximum-effort cycle exercise on an incremental ramp protocol (2016-2019), with blood drawn at rest (n=471) and at peak exercise (n=411). The average age of the sample was 53 years.

Changes in the Metabolome

Over about 12 minutes of exercise, 85% of the 588 measured metabolites shifted dramatically, with beneficial alterations observed in levels of metabolites representing metabolic pathways central to obesity, insulin resistance, oxidative stress, inflammation, vascular reactivity and longevity. Numerous examples are detailed in the article.

In a replication sample of 783 Framingham Heart Study participants, the researchers observed similar changes in 93% of the 177 common metabolites.

Intriguingly, shifts in many of these metabolites were unrelated to the exercise workload achieved. This suggests that even brief exercise produces a healthier metabolic state.

Determinants of Changes

Exercise-induced changes in several metabolites were significantly influenced by body mass index (BMI), even after adjustment for the workload. For example, individuals with higher BMI had less reduction in dimethylguanidino valeric acid (higher levels are associated with hepatic fat). Favorable metabolite shifts may be blunted in those with higher BMI, conferring resistance to the benefits of exercise. Differences in metabolite excursions with exercise were also observed for men and women, with women displaying greater favorable changes in certain metabolites involved in cardiometabolic health.

Exercise-associated changes in metabolite levels were consistent across a broad spectrum of ages, consistent with previous research showing different age groups may benefit from exercise similarly.

Metabolite Signatures

Resting metabolite levels were distinctly associated with different physiologic exercise responses, linking metabolic dysfunction to different domains of exercise performance. For example, different metabolites were associated with peak oxygen consumption (representing cardiorespiratory fitness and global metabolic health) and ventilatory efficiency (VE/VCO2, which reflects central cardiac performance and pulmonary vascular function).

The researchers combined exercise testing variables (peak heart rate, peak oxygen uptake, aerobic efficiency, etc.) with metabolite profiles to create metabolic signatures of integrated physiologic responses to exercise. The associations of these metabolic signatures and long-term outcomes were then tested in 2,045 members of a separate Framingham Heart Study cohort with long-term follow up (Second Generation, average age 55, median follow-up 23 years). They found that two of the four metabolite signatures predicted mortality, even after adjustment for cardiovascular disease risk factors.

Laying the Groundwork for New Interventions

This study provides a detailed analysis of the metabolic architecture of acute exercise and identifies specific metabolic pathways that are related to both responses to exercise and to long-term mortality.

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Massachusetts General Hospital researchers have identified a set of proteins specific to heart failure that might help diagnose the disease, evaluate treatment response and identify drug targets.


In this video, Matthew Nayor, MD, cardiologist in the Heart Failure and Transplantation Program in the Corrigan Minehan Heart Center, discusses his research on identifying and predicting heart failure using data from the Framingham Heart Study to understand protein measurements in blood.