Exercise training will help health and performance. But will too much exercise do the opposite? This was the topic of debate in the media and amongst scientists after a publication by Flockhart recently. This blog will discuss a counterpoint made by Hawley and Bishop who critically counter the conclusions by Flockhart.
Exercise training is a powerful stimulus for improving the function of mitochondria, enhancing both health and exercise performance. However, a recent study by Flockart et al., (1) suggested that training too hard could have negative effects. This provoked responses from a number of researchers including John Hawley and David Bishop. They criticised the study and its conclusions in a commentary. Here we will look at this commentary and draw our own conclusions.
In their paper Flockhart et al suggested that there might be an upper limit to how much training can be performed before markers of health and performance begin to stagnate or deteriorate (read the summary: ‘Excessive exercise training affects performance, mitochondrial function & glucose tolerance: A summary of Flockhart et al., (2021)’). These findings received a lot of attention in the media and researchers Hawley and Bishop responded with a commentary (2). Below is the summary of this commentary before we wrap up and draw our own conclusions from these publications at the end of this blog.
High intensity interval training (HIIT)
Hawley and Bishop discuss that HIIT provides a powerful stimulus to the various systems that support exercise, including the muscles themselves. Exercise results in the process of mitochondrial biogenesis, the growth and formation of new mitochondria. This was definitively shown in studies by the researcher John Holloszy in the 1960s and beyond, who used HIIT protocols in rats to demonstrate that a minimum ‘threshold’ of exercise had to be achieved before adaptations took place. Though all exercise has a plethora of beneficial health outcomes, HIIT appears to be particularly effective at improving markers of metabolic health.
The ability of exercise to prevent and treat disease has led to the idea of ‘exercise as medicine’. Unlike other medicines, the exact ‘dose’ of exercise required for various outcomes is not well understood. Flockhart et al., suggest that there may be an upper limit to the amount of HIIT that can be performed before disruption to homeostasis and mitochondrial dysfunction occur.
Hawley and Bishop argue that a shortcoming of the study is related to the exercise model used, which was a very ‘one dimensional’ approach, incorporating a training program of only HIIT. This is uncommon for both athletes and recreationally active people, who generally choose from a broad ‘menu’ of different exercises, exercise types and modalities.
Measuring the mitochondria
The main measure of mitochondrial function that was used (IMR) was performed using isolated mitochondria – mitochondria extracted from the muscle biopsies that were taken. Because of the intensive processing steps and the small number of mitochondria found in the muscle, these extracts contain only a small proportion of the total mitochondria. This means that these mitochondria may not be representative of the whole ‘pool’ in the muscle. Studying mitochondria in isolated, extracted muscle fibres is a more realistic way of looking at mitochondria, with their normal structure and location. In fact, one study (3) showed that when comparing these 2 methods, the isolated method leads to higher & exaggerated results.
What is the validity of the measurements?
The finding of a 40% reduction in IMR was actually halved to 20% (and made no longer statistically significant) when expressed relative to citrate synthase activity from the same samples. This suggests that the activity of the enzyme reduced, but when this was compared to the same measurements from the muscle biopsy before the mitochondria were isolated, the citrate synthase activity actually increased! A different study by Dave Bishops’ team (4) recruited similar subjects and put them through a more demanding training program, and actually saw increases (of 20-50%) in IMR using the more reliable isolated muscle fibre technique.
Timing is crucial
A short-term investigation like this only provides a ‘snapshot’ of the various responses to the training. Muscle biopsies were taken at specific times that may not represent the wider biological state, such as 14 hours after the final exercise session. This reduction could be part of a ‘rebound’ that occurs in many measures after exercise as part of the supercompensation model. This idea has weight, as other studies have shown that 72 hours after high volume intensified training, mitochondrial respiration increases (also using the more reliable isolated muscle fibre technique).
Molecular responses versus whole-body responses
Although the study showed both reduced IMR and reduced glucose tolerance, and that they were correlated, the relationship was weak. This makes it hard to know whether they are linked, and whether, perhaps the reduced IMR was the cause of the reduced glucose tolerance. The reduction in glucose tolerance is strange, especially considering that at this timepoint, the levels of GLUT4 (the protein responsible for shuttling glucose into cells) was highest. This mismatch between the high-resolution molecular response and the practical whole-body response is common, though many studies focus on only one or the other.
The study by Flockhart et al., further demonstrates that we still do not understand the ideal amount of exercise for improving metabolic health and fitness. It also shows that the findings from cells, tissues and the whole body must be integrated coherently so that the information can be used in recommendations for exercise.
when interpreting study findings, such as those by Flockhart et al., it is important to consider the methods used to collect data and determine the application of these findings to, for example, a real-world scenario.
So, what can we conclude?
So, what can we conclude from these 2 publications? The Flockhart et al is a classical example of a study being designed to look at a “proof of principle”. The study looked to study a specific question and a study was designed to test the hypothesis that was formulated. In doing so, the study design became more extreme and less practical. This, however does not invalidate the findings... it just means that we must be careful with interpretation and extrapolation. Similarly, with the OGTT test results that were obtained. Is a high blood glucose concentration in elite athletes really comparable to chronically high blood glucose in patients with diabetes? The glucose concentrations in elite athletes are not chronically high, they are occasionally high and elite athletes train more and eat more and none of these factors are taken into account, so we are really comparing apples and pears here. All in all, I think the research by Flockhart et al shows really interesting and novel information. It helps us to form new hypotheses. We must now study whether we see the changes they observe in real life conditions. Ideally, we confirm findings in different labs and with different methods. The total picture will help us to understand what is really happening. Every single study is important and they are pieces of the puzzle. But most pieces on their own don’t tell us much about the bigger picture.
We must also find out whether what is referred to as “mitochondrial dysfunction”, which suggest that it is not part of normal physiology but rather pathophysiology, is actual part of normal physiological adaptation. As an analogy, free radical production and inflammation, can also be linked to disease, but they are required for normal training adaptation. So as scientists often conclude: more research is needed… we need more pieces of the puzzle to really understand the bigger picture. We should not ignore the bigger picture, by focussing on one piece. At the same time should also not ignore the individual pieces of the jigsaw, especially not, if they were carefully obtained.
although most studies don't tell us much about the bigger picture on their own, each study is important and acts as a piece of the puzzle.
As a final note, there is nothing wrong with the Flockhart study which we discussed here. But the results may have been a little over interpreted. On the other hand Hawley and Bishop make some critical but good points but doesn't mean that the study results can be dismissed. This is a great example of how science works and should work. let continue the debates and the studies so that more pieces of the puzzle will bring us closer to the truth.
References
Picard M, Ritchie D, Wright K, Romestaing C, Thomas T, Rowan S, Taivassalo T, Hepple R. Mitochondrial functional impairment with aging is exaggerated in isolated mitochondria compared to permeabilized myofibers. Aging Cell. 2010;9:1032-46.
Granata C, Caruana N, Botella J, Jamnick N, Huynh K, Kuang J, Janssen H, Reljic N, Laskowski A, Stait T, Frazier A, Coughlan M, Meikle P, Thorburn D, Stroud D, Bishop DJ. Training-induced bioenergetic improvement in human skeletal muscle is associated with non-stoichiometric changes in the mitochondrial proteome without reorganization of respiratory chain content. 2021.
