Effect of Chronic Exercise in Healthy Young Male Adults: A Metabolomic Analysis

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ByCrossFitMay 18, 2020

Question: What are some of the primary metabolic changes that occur alongside an extended exercise program?

Takeaway: This trial found an 80-day exercise program, administered to newly enlisted Army recruits, improved measures of muscle lipid metabolism and vasodilation. One marker, DMGV, was found to predict a poor metabolic response to exercise.

This 2020 paper aimed to provide the most highly controlled analysis of the impact of exercise on specific biomarkers to date.

Fifty-two newly enlisted male Army recruits (average age: 22 years) agreed to participate in an 80-day exercise program. Recruits averaged 1.3 hours of exercise per day, 68% of which was moderate and 32% of which was high intensity. The intervention included endurance and resistance training alongside occupational activities such as marching.

This study was unique in that all recruits were living in the same domicile, which limited variations in sleep, stress, diet, and other factors. The subjects were not compared to a control group, however, so any differences between these factors and what recruits had experienced prior to enlistment may have influenced the outcomes.

The study analyzed 201 metabolites, and statistical significance was assessed at p < 0.0004 after Bonferroni correction. All samples were taken in the early morning after an overnight fast. Consistent metabolite shifts included:

  • Reduction in a variety of lipid synthesis and metabolism intermediates, including malonate, cell membrane arachidonic acid, and various fatty acid derivatives;
  • Reduction in ketone levels; and
  • Elevated levels of arginine and markers of arginine metabolism.

The authors interpreted decreased lipid and ketone levels as indicative of increased muscular beta oxidation (i.e., fatty acid metabolism) efficiency and capacity. This is consistent with previous research suggesting exercise improves the body’s use of muscular fatty acids and ketone bodies, and that this phenomenon directly contributes to the improvements in lipid profile associated with exercise (1). Elevated levels of arginine and related metabolites indicate improved vasodilation and blood flow in response to exercise (2).

Figure 2: Human cohort (A–D). *P < 0.05, **P < 0.01, ****P < 0.0001. (A) Indole-3-propionate, a microbiome-derived tryptophan metabolite, significantly increased post-exercise (P < 0.0001). (B) Lipid metabolites, including malonate (P < 0.0001), arachidonate (ARA, P < 0.0001), ketone body (BHBA, P < 0.0001), 2-arachidonylglycerol (2-AG, P < 0.01), and secondary bile acid taurodeoxycholic acid (TDCA, P < 0.01), significantly decreased post-exercise. (C) Arginine-related metabolites arginine (ARG), ornithine (ORN), dimethylguanidino valeric acid (DMGV), and NG-monomethyl-L-arginine (L-NMMA) all significantly increased post-exercise (all, P < 0.0001). (D) Plasma levels of threonine (THR) and homoserine (HSE) significantly increased (both P < 0.0001), and α-ketobutyrate (α-KB) significantly decreased in human exercise cohort (P < 0.0001). Data are expressed as the mean (± SEM) with N = 52 biological replicates in each group. All data are analysed using paired t-test.

The authors also noted one biomarker, DMGV, predicted a suppressed biological response to exercise. Previous research has found elevated levels of DMGV are correlated with and may predict fatty liver disease and diabetes (3). In the same studies, DMGV was associated with increased visceral adiposity and reduced insulin sensitivity. In this study, higher baseline DMGV levels predicted smaller improvements in body fat, blood pressure, and a variety of lipid markers, which is consistent with previous data and suggests those with higher DMGV levels may see reduced benefit from exercise. The authors noted currently unpublished data suggests sugar-sweetened beverage intake may increase DMGV levels.

Overall, this cross-sectional study indicates exercise improves lipid metabolism and vascular function in less than three months in young, healthy males. Other forms of exercise may lead to a different pattern of improvements than what was observed here.

Comments on Effect of Chronic Exercise in Healthy Young Male Adults: A Metabolomic Analysis

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Tyler Hass
May 19th, 2020 at 7:31 pm
Commented on: Effect of Chronic Exercise in Healthy Young Male Adults: A Metabolomic Analysis

Interesting study with some expected findings, like increased fatty acid and ketone body utilization. And some unexpected, like decreased endocannabanoid levels (these are what decrease pain during exercise and produce the runner's high). The DMGV hypothesis is interesting. This metabolite increased in those with a blunted response to exercise. This sounds fatalistic, but at the end of the paper, they mention unpublished research suggesting sugar sweetened beverage consumption can increase DMGV, while exercise and vegetable consumption can decrease it. That's a future paper worth keeping an eye on.


Earlier research has demonstrated the existence of adverse responders to exercise. These people see increases in blood pressure, HDL, TG, fasting insulin or more than one of these. Nathan Jenkins (!) was involved in this study: Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence?

In an analysis of several previous studies, they found worsening fasting insulin in 8.4% of subjects, higher blood pressure in 12.2%, 10.4% for triglycerides and 13.3% for HDL-C. One thing they found is that the people who responded adversely in regards to these health biomarkers also experienced the least improvement in performance metrics, like VO2max. DMGV might be a mechanism that could explain some adverse results.


Somewhat related, one study refuted the idea of non-responders: Refuting the myth of non‐response to exercise training: ‘non‐responders’ do respond to higher dose of training

As exercise volume increased from one to five days a week, non-responders eventually disappeared. They were tracking performance only, and not health biomarkers. The first study I mentioned above did not see this type of dose-response. Adverse responders were seen in roughly similar amounts at all exercise volumes.


The DMGV mechanism offered by this metabolomic study offers perhaps more weight to the idea that you cannot outrun a bad diet. For adverse responders, a more comprehensive approach to health might be required. And thankfully, CrossFit is all over that.

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Grant Shymske
May 20th, 2020 at 5:23 pm

Wow Tyler, really interesting insights and references. Thank you for sharing and elaborating on this topic.

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Alex Broadbent
May 24th, 2020 at 5:44 am

Very interesting insights. What do you think about quantity of exercise? These are trainee soldiers and 1.3 hours exercise a day is thus feasible and perhaps enforceable by peers and superiors. Triathletes may clock up that amount of training but few other civilians will do so. It would be interesting to know whether lower volumes of exercise have similar effects. Of course the idea behind CrossFit is that intensity is as important or more important than volume. It would be interesting to do this with a less time consuming program.

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Tyler Hass
May 24th, 2020 at 6:46 pm

That’s a great question on intensity vs volume. I'd love to know the answer, as it's still a bit of a mystery. It’s pretty clear that people respond differently to resistance training. There are some people that respond better to volume and others to heavier lifting. CrossFit is obviously a hybrid of both approaches.


The two studies below shed some light on the non-responder phenomena with regards to resistance training.

Cluster analysis tests the importance of myogenic gene expression during myofiber hypertrophy in humans

In this study, the participants are training 3x per week doing 3 lower body exercises (leg curls, leg extensions, leg presses) and 3 sets of each to failure (8-12 reps). This is pretty high volume training. There was a continuum of non-responders to extreme responders. A lot of the responsiveness correlated to age and gender.  However, there were big differences in gene transcription as well. This would suggest a genetic or epigenetic component to responsiveness.


A later study by the same research group found some interesting results, which I’ve quoted below. It suggests that non-responders have a pro-inflammatory response to exercise that inhibits training adaptations. They might be experiencing greater muscle damage due to exercise. If that's the case, it might just mean they need more time under the bar. As muscles become better trained, the amount of muscle damage experienced during exercise decreases and the training adaptations increase. So, non-responders might be delayed responders. The short duration of typical studies might not catch this.


Cluster analysis reveals differential transcript profiles associated with resistance training-induced human skeletal muscle hypertrophy

“Expression differences between Xtr and Non suggest Non could have heightened localized inflammation that may interfere with the ability for skeletal muscle to respond to a hypertrophic stimulus. Several of the differentially expressed genes that were upregulated in Non are associated with NF-κB signaling, a pathway known to be linked with heightened inflammation and skeletal muscle atrophy (28). Genomic signatures that suggest heightened inflammation and inflammatory and metabolic dysfunction have been demonstrated in other populations, which might also have an impaired growth capacity (36, 39).”

“The molecular profiles suggest responders benefited from enhanced transcriptional regulation, myogenic and satellite cell function, and muscle growth signaling, while individuals who did not experience RT-induced myofiber hypertrophy expressed a profile indicative of enhanced inflammatory signaling.”


I think CrossFit’s Mechanics-Consistency-Intensity model is the right way to go. Good mechanics and a level of volume/intensity that can be trained consistently will help to minimize muscle damage and inflammatory responses. Over time, increasing the intensity will deliver adaptations. Some people will progress faster than others, but I think the vast majority of people will eventually see beneficial results. Unfortunately, the people who respond adversely to training are probably the most likely to drop out before they overcome whatever is causing their non-responsiveness. Lifestyle (poor diet, lack of sleep, stress) probably also plays a huge role.

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