I’ve been interested in how people respond differently to exercise because I want to prescribe exercise as medicine. I’m going to keep this post wicked short because I haven’t read this whole paper yet, or had time to digest it as it’s almost finals week for me and I don’t have time. But I have saved it to my folders because this is pretty novel stuff.

This paper found that 21 different genes explained half of the variations in the heterogeneous responses of V02 max in response to aerobic exercise training. Some of these genes help people use fatty acids as fuel more effectively, and some just make their mitochondria more active. I’ll have to talk about this paper in detail another time.

Next week I will start getting back to the topics of health myths and disordered eating. Stay tuned.

I’m very interested in personalized medicine; in order to personalize it however we need to know how people are different, to put it as simply as possible. When I worked as a personal trainer in Washington D.C. during my college years, I quickly realized that some people happened to like certain exercises more than others. This sounds obvious, but its implications to me are that perhaps their liking of certain exercises more than others indicates that it’s better for them. This applies to nutrition as well; we are well-adapted to recognize odors and tastes that could indicate something harmful. So for a while I’ve been thinking that some people do better with low intensity exercise (relaxed hikes, recreational sports for fun, playing outside, walking) and some prefer and respond better to higher intensity exercise (competitive sports, crossfit, rigorous weight-lifting, etc). Ayurvedic doctors suspected the same things, but they recommended that we do the opposite of what we prefer once in a while, to balance ourselves out.

So the study I want to talk about today was the first (generally when researchers submit their protocols they like to emphasize that what they are doing hasn’t been done before, so this study apparently wasn’t done before) to look at individual differences in the change in VO2 max (the maximum amount of oxygen one can use in a given period of time) after exercise training. The subjects (481 of them) trained on a cycle ergometer, or stationary bike, three times a week for 20 weeks.

The results were that some people improved their aerobic capacity a ton, and some almost not at all. And as the researchers knew before already, in twin studies, the variation in the change in VO2 max between groups of twins is much higher than the variation between twins, in response to aerobic exercise training. Here they found the same thing among families. This figure sums up their findings.

Here’s the main point:

THERE’S SOMETHING GENETIC THAT CAUSES SOME PEOPLE TO SEE A GREATER INCREASE IN VO2 MAX AFTER AEROBIC EXERCISE TRAINING THAN OTHERS!! In the near future I’ll mention that this heterogenous response also applies to things like LDL and HDL cholesterol, which gets us a little closer to theorizing how this all affects disease progression.

But what are the implications of this study then? Well I kinda hinted at that-ish last week when I discussed an amazing paper on rats that found that the low-responders saw a greater inflammatory response to exercise and the high responders showed a higher anti-inflammatory response. (It would make more sense to post this study first but this is kind of background for that, so if you didn’t catch last week’s post, go click on it in the hyperlink I provided). If that can be shown in humans, it would give me a mind-gasm. I’m sure there are some studies that provide clues to this but I don’t know of them at the moment.

Next week I plan to discuss some of the genes that have been identified after this study that explain the heritability and differences in response to aerobic exercise training. Some of you may be wondering: does this apply to resistance exercise? Considering that a lot of people are into things like crossfit and doing a mix of aerobic and resistance exercise, it’ll be important to come up with a design that can look at that. For now, I don’t know; but I sure think that there is a genetic component, as I kind of mentioned in my introductory paragraph, where I noticed that some people just liked certain exercises more than others and maybe that indicates they would flourish at them. I like sprinting and anaerobic activity so I’m going to do some sprints right now.

One of my qualms working as a personal trainer in my broke college days was fueled by my ignorance of my clients’ health. I trained a lot of overworked, stressed, and baggy-eyed clients in Washington D.C. back then (just a couple years ago), and I knew that some of these people needed to reduce their stress levels in order to lose weight and feel more energized, and intense exercise probably wasn’t the right prescription.

Yet I prescribed strength training mixed up in a circuit format, having my clients perform upper body and lower body compound-movement exercises in succession with little rest. They got sweaty, and fatigued, and some of them had bloodshot eyes after their workouts. I myself had them because I believed in doing really intense exercise all the time as many personal trainers do. As I’ve talked about previously, it led adrenal issues that I never got diagnosed correctly, so I can only guess when I say it was an adrenal issue.

What I really wanted to do as a personal trainer I couldn’t do until I became a doctor. I wanted to know my clients’ past medical history, be able to look at their blood work, and even look at their genome. I wanted this information in order to predict what will happen to them with exercise training. Simply observing physical changes isn’t enough. Even though in many cases people lose weight, keep it off, and seem to be a lot healthier and happier, many people lose weight and feel worse. How this works I am not entirely sure yet.


So that’s why I was very intrigued by the paper I want to discuss today. I had a feeling for a while that not everyone responded to exercise the same way. I learned in my exercise physiology classes early on that some people’s aerobic capacity didn’t change at all in response to endurance exercise training. And as data from the HERITAGE Family Study pointed out, a lot of this is heritable.


The paper I am discussing today, “Resistance to Aerobic Exercise Training Causes Metabolic Dysfunction and Reveals Novel Exercise-Regulated Signaling Networks,” delved deep into the mechanisms behind what separates low-responders to aerobic exercise from high responders. They made a bunch of rats (n = 152) complete eight weeks of treadmill running three times a week. Then they identified those who improved their fitness the most and the least using an incremental treadmill running test.

They bred the rats that had the highest response to training (HRT) and the lowest response to training (LRT) with each other for 15 generations to make really fit rats and really not fit rats that probably did not want to do what came next. Next, 10 rats from each group completed the three times a week for eight weeks exercise training session that their great-great-great-great-great-great-great-great-great-great-great-great-great grandparents completed at the beginning of the study. Another ten from each group served as a control.

The researchers here wanted to know if the LRT rats had any differences in their metabolism even without exercising, AND how it changed with exercise. What they found was pretty shocking, to me at least. First of all, the LRT rats saw a decrease in how far they could run AFTER TRAINING. That should have you scratching your head. It’s as if these rats were so sick of running they just didn’t care anymore. That you can see in panel C. The LRT rats decreased how far they could run by 65 meters, which was about 10% of what they started with. Whereas HRT improved their exercise capacity by 54%.

Next, the LRT rats displayed “whole-body metabolic dysfunction” without even exercising, as displayed in the figure below. Let’s go through it a little bit.

In panel B, the rats’ glucose tolerance is displayed. This is assessed by feeding the rats glucose and monitoring how much glucose remains in their blood over a two hour period. Generally, if the area under the curve (AUC) in one group is lower, it means that the rats’ tissues are able to slurp up the unbeknownst to them injected glucose better than the other group. HRT here displayed a smaller AUC than LRT at all time points, showing that they were more insulin sensitive.

In panel C, the glucose levels after an injection of insulin, is displayed. Insulin is the hormone that unlocks the keys to the gates that allow your body’s tissues to use the glucose in your blood after an ingested meal usually. This causes a lowering of blood sugar. But if you’re insulin resistant, an injection of insulin won’t lower blood glucose much. That’s what was observed in panel C in the LRT rats, suggesting of course that there is something genetic about their fitness levels and ability to process glucose.

And most interestingly in this figure to me, is the data in panels G and H. After exercise training for eight weeks, the rats from the unfit, or as these authors termed it, “exercise-resistant” family, had higher levels of TNF-α, a pro-inflammatory cytokine and lower levels of TGF-β1, an anti-inflammatory cytokine. Their liver triglycerides also went up after exercise training, whereas the HRT’s triglycerides went down slightly.

If this can be shown in humans then I think it would be pretty huge.

The researchers wanted to know how this was happening, so measured a LOT of other stuff. They found several other things which I’ll just summarize:

  • LRT rats displayed 50% less capillary density in their muscles AFTER exercise training compared to HRT. Before training the capillary density was the same.
  • LRT rats had fewer type I muscle fibers than HRT fibers. These are the slow-oxidative muscle fibers that are important for endurance training. They had fewer fibers before exercising so the authors said this factor couldn’t explain the post-exercise differences.
  • Mitochondrial enzymes (citrate synthase) however were not markedly different between the two groups.
  • “Oxygen consumption, the respiratory exchange ratio, muscle glycogen concentrations, and serum free fatty acid concentrations were similarly altered by exercise in LRT and HRT.” What this means is that the LRT displayed a normal response to an ACUTE bout of exercise. Just a note here: the term exercise by itself refers to an acute bout of exercise whereas exercise training must be denoted to indicate a period of exercise training. Sounds obvious but it gets interchanged a lot and it’s not supposed to be according to exercise physiologists.
  • There’s this molecular signaling pathway called AMPK that mediates some of the benefits of exercise. There was no difference here among LRT or HRT.
  • GENES were differently regulated among the two groups was different after exercise. They get much more detailed about this in the paper and it’s beyond my current education at the moment but it looks like something fun to research and talk about at a future time. But basically the response to exercise in LRT was a lot different than in HRT and gave insight into some of the mechanisms.


I have a feeling that low-responding humans probably don’t force themselves to run three times a week so they get to avoid increases in pro-inflammatory cytokines that might accompany endurance training that they’re not meant for. This exact question, is exercise really beneficial to everyone, is something I want hashed out in more detail.

Next week, I’ll stick to this topic and look at another paper.