There are few things that just about everyone in the health and nutrition professions agree on. Things that were once accepted at face value have come under scrutiny in recent years—such as what constitutes a “heart-healthy diet,” whether increased dietary fiber is beneficial for constipation, and whether it’s always prudent to use medication to lower LDL cholesterol. However, one recommendation that has stood the test of time is that physical activity is a good idea—for physical and mental health, and even for cognitive function. Most experts agree that exercise is “good for you,” but that’s a broad, general statement. Research published recently reveals new details about the effects of exercise on metabolites that may indicate improved overall fitness and metabolic efficiency. 

The study was conducted in Australia and published in Cardiovascular Research, a journal of the European Society of Cardiology. Subjects were 52 young men (mean age 22 ± 4) enrolled in the Army Recruit Course. The intervention consisted of 80 days of physical training which included a combined strength and endurance program plus marching. Average total physical activity time per week was 9.3 hours (about 1.3 hours per day), 68% of which was classified as moderate intensity and 32% classified as high intensity. Early morning fasting blood samples were taken at baseline and after the 80-day program, and changes in levels of 95 metabolites were detected adequately in plasma and reported on. 

Studies evaluating the effects of exercise on various biomarkers are nothing new, but this one has a particular strength going for it. By choosing army recruits as their subjects, researchers were able to control for several normally confounding factors:

“Most metabolomic studies of exercise have occurred in the setting of volunteers undergoing exercise interventions in an institution, then returning to their usual lifestyle. In chronic exercise training programmes, environmental exposures are typically not controlled during the course of the training programme that usually occurs over several weeks.

Many factors differ considerably in these individuals, including those deriving from diet, work environment, stress, socioeconomic status, and sleep. Therefore, we designed a study whereby these confounding environmental factors could be controlled. Consequently, we used soldiers of similar age and body mass index (BMI) who resided in the same domicile, ate the same food, had the same sleep routine, and performed the same daily activities.”

No study is ever perfect, but controlling for multiple lifestyle factors known to have profound effects on health is a big step in the right direction. 

Looking at the results, overall, subjects showed a small but statistically significant decrease in BMI (24.04 ± 3.14 at baseline versus 23.54 ± 2.18 post-intervention), a significant decrease in body fat percentage (15.5 ± 4.5 baseline; 12.5 ± 3.1 post), and a significant increase in estimated VO2 max, indicating improved respiratory fitness. Not all subjects experienced these changes, though—a detail we’ll look at shortly. 

Highly significant decreases in several intermediates of lipid/fat metabolism were observed post-intervention, including nine-fold decreases in the ketone body beta-hydroxybutyrate and malonate (an intermediate of lipid metabolism). Increases were seen in circulating arginine, ornithine and other compounds related to arginine metabolism, while a two-fold decrease was seen in phytonadione—vitamin K1—which is involved in synthesis of clotting factors. 

All of these changes have reasonable explanations. Exercise-induced increases in arginine and ornithine are likely related to improved vascular function potentially stemming from increased nitric oxide synthesis. Regarding the decrease in phytonadione, study authors wrote, “Exercise leads to activation of both coagulation and fibrinolytic cascades, and in the post-exercise period fibrinolysis returns to normal, whereas coagulation was shown to remain elevated up to 1-day post-exercise. The decreased plasma phytonadione (used in the formation of clotting factors) we observed may well be as a result of sustained activation of the clotting system on the day following the exercise training programme ended.” 

The dramatic reductions in plasma fatty acid and ketone body intermediates are a bit more puzzling, but only on the surface. After undergoing a rigorous physical training regimen, one might expect to see increased ketone bodies and fatty acids in the blood, because subjects would be expected to be oxidizing fat and generating ketones at a relatively high rate. This is precisely why these levels were decreased, however: these two substrate classes are “consumed more by trained, energy efficient skeletal muscle,” – in other words, subjects’ muscles were hungry for fuel and may have readily taken up fatty acids and ketones from the blood, which would have precluded these compounds from accumulating in the blood. As the researchers explained, “Ketone bodies are oxidized as a fuel source during exercise, are markedly elevated during post-exercise recovery, and the ability to utilize ketone bodies is higher in exercise-trained skeletal muscle. Therefore, exercise-trained skeletal muscle will utilize ketone bodies to a greater capacity than the untrained muscle, explaining its reduction in plasma.”

Interestingly, not all subjects responded so favorably to the training regimen. These were young, healthy men, yet some of their metabolic profiles appeared to get worse. A compound called dimethylguanidino valeric acid (DMGV) was identified by other researchers as being “associated with attenuated improvements in lipid traits and insulin sensitivity after exercise training” among previously sedentary individuals. This finding was replicated among the army recruits: researchers noted, “even in young, healthy, and fit adult males, DMGV’s relationship to poor metabolic response to exercise persists,” and they propose that DMGV could potentially be used “as a marker of subclinical metabolic dysfunction even in low risk and apparently healthy individuals.”

Increased DMGV was associated with increases in blood pressure, triglycerides, total and LDL cholesterol, fasting insulin and blood glucose, HOMA-IR, BMI and body fat percentage—precisely the things you would expect to improve after an exercise intervention. (Increases reached “significance” only for body fat, total and LDL cholesterol, and systolic blood pressure.) Individuals who show less-than-expected improvements, no change, or possibly adverse changes in response to exercise are termed “non-responders” or “low responders.” It’s unlikely that there are truly non-responders; it may be that these individuals require a higher level of intensity, frequency, volume, or duration of activity in order to exhibit the beneficial changes others experience more readily. (Anyone who’s ever trained with friends or in a group setting knows individual responses are highly variable!) Or, these low- and non-responders may respond more powerfully to interventions addressing other lifestyle factors beyond increased physical activity. (DMGV is likely not causing the worsened metabolic profile; it is just an associated marker/indicator that may help predict those who are more likely to be non-responders.)

The study wasn’t without weaknesses. Most notably, all subjects were male, young, healthy, and started with a high level of fitness at baseline. The metabolomic findings would need to be replicated in older individuals, women, and those with poorer health in order to see if these changes are generalizable to a wider population. If they are found to hold true in other populations, though, it would mean people can expect increased fat burning, ketone usage, improved vascular function, healthy protein turnover, favorable changes to body composition and more. (But perhaps this confirms what we already knew!)