As we have discussed at length in the past, some of the fundamental physiological adaptations sought by endurance athletes through training occur in the mitochondria. A textbook will tell you that the mitochondria are the ‘aerobic powerhouses’ of cells; the sites of aerobic metabolism, and therefore metabolically where an endurance athlete makes their money. It has long been known that significant mitochondrial remodelling occurs in response to exercise (4), with increased size, number, and functionality of mitochondria observed following endurance training (5). This mitochondrial remodelling, and subsequent useful increase in the mitochondrial respiratory capacity, typically occurs as a result of mitochondrial biogenesis – the building of nice new mitochondria – and mitophagy – the break-down of damaged existing mitochondria.
A couple of recent studies have reported quite startling findings; namely, that short periods of very intense training actually degraded certain measures of mitochondrial function (1, 2). Specifically, these studies suggested some level of dissociation between adaptations to mitochondrial respiratory capacity – how much oxygen the mitochondria of the study subjects could maximally consume - and mitochondrial protein content – how much mitochondrial protein the study subjects had. The interpretation of these findings has some very important and challenging nuances, and, unsurprisingly, these studies generated a lot of discussion in our community. In this blog, we will try to briefly break these results down.
What do recent studies show?
The first study we want to discuss was published by a group of Swedish researchers in the prestigious journal Cell Metabolism (2). In this study, a group of active volunteers performed a block of high-intensity interval training with progressively increasing volume over three weeks, followed by a reduced volume "recovery" week. Muscle biopsies were obtained at the end of each week for assessment of mitochondrial protein content and function. Note that the participants were not athletes and that by week three their training included three 5 x 8 min interval sessions and two 5 x 4 min interval sessions. So, the training intensification we are talking about here is quite substantial.
During the study, mitochondrial respiratory capacity initially increased but decreased in the third week of the intense training programme. There was then some recovery of mitochondrial function in the reduced volume ‘recovery’ week, which still included four HIIT sessions (3 x 8 min, 3 x 4 min, 3 x 8 min, and 5 x 4 min), though only to baseline values rather than those observed after week two. The conclusions of the study were therefore that excessive exercise training might actually impair mitochondrial function, at least temporarily.
Before we read too much into this interesting – excellent - study, we should acknowledge the critique of it made by Professors John Hawley and David Bishop. Hawley and Bishop recently published a letter in another prestigious journal - Nature Reviews Endocrinology - in which they questioned the methods used by the Swedish group (3). In particular, the Cell Metabolism study assessed mitochondrial function by extracting isolated mitochondria from their muscle biopsy samples - and this technique may not properly capture how the mitochondria would function within muscle tissue in vivo (i.e. in an exercising person in the real world). They also suggested that the observations made by the researchers may have been an artefact of the sampling time-points and that the proximity to the previous training session may have impacted the outcomes. We should point out here that this critique was very collegial, and simply in the spirit of open discussion of excellent science.
The critique turned out to be very timely, as another paper was then published – this time in the Journal of Applied Physiology – only a few weeks later (1). In this study, mitochondrial adaptations were measured in response to intensified training in a cohort of 27 highly-trained endurance athletes. The athletes performed their normal training for four weeks, with the addition of three weekly high-intensity interval training sessions, and muscle biopsies were obtained before and after the intervention period. Before we discuss the mitochondrial adaptations observed in this study, it is worth considering that V̇O2max and 30-min time-trial performance both improved as a result of the intensified training intervention (as one might hope!).
Let’s break down the mitochondrial adaptations. There was firstly strong evidence of mitochondrial biogenesis or an increase in total mitochondrial protein content within the samples. This was assessed in a number of different ways, all telling the same story (increased citrate synthase enzyme activity, OXPHOS complex I and II abundance, and mitochondrial volume density assessed by transmission electron microscopy – although this last measure was only made in a small sub-set of samples – if you are interested). However, despite this increase in mitochondrial protein content, there was also evidence of reduced mitochondrial respiratory capacity; that is, maximal mitochondrial respiration – expressed per unit of muscle – and these measures were made in permeabilised muscle fibres (in line with the recommendations made in Hawley and Bishop’s critique and in contrast to the isolated mitochondrial measures in the previous study). Given that there was more mitochondrial protein per unit of muscle, and mitochondrial respiratory activity per unit of muscle was reduced, there was also evidence of what the authors called reduced mitochondrial ‘quality’ – mitochondrial respiratory activity expressed per unit of mitochondrial protein decreased.
To an exercise physiologist, these results are terribly interesting and do support the results of the Cell Metabolism study suggesting that short periods of very intense training might temporarily impair mitochondrial function. The mechanism behind this effect is not established but may be related to the cellular stress generated in the short period of intense training damaging some mitochondria – part of the adaptive process – and the muscle not being able to keep up and break down damaged and less useful mitochondria – a process called mitophagy – at the same rate. Therefore, the presence of some damaged and less capable mitochondria in the muscle samples taken after the period of intensified training may have dragged down measures of respiratory activity temporarily. It is hard to ask for more information from such a high-quality study, but it does remain possible that had a third muscle sample been obtained another week later, mitochondrial respiratory activity may have increased due to the greater time allowed for damaged mitochondria to be mopped up.
What do we need to know next?
That was a lot of science and a lot of information. What can we make of it? The idea that "excessive" training and stress may temporarily impair physiological function is an intriguing one, and a situation we generally seek to avoid as long-distance triathletes through management of training stress using careful monitoring of training load and intensity distribution. The training programmes used in these studies are not ones we would recommend athletes use for long periods, although block training can work under certain circumstances. It would be very interesting to assess how mitochondrial function – and, importantly, exercise performance – responds to these types of training stimuli with a ‘taper’ week included at the end.
Either way, these results were super interesting and valuable for our community, and will be the subject of discussion for years to come!
1. Cardinale DA, Gejl KD, Petersen KG, Nielsen J, Ørtenblad N, Larsen FJ. Short term intensified training temporarily impairs mitochondrial respiratory capacity in elite endurance athletes. J Appl Physiol 2021 (ahead of print).
2. Flockhart M, Nilsson LC, Tais S, Ekblom B, Apró W, Larsen FJ. Excessive exercise training causes mitochondrial functional impairment and decreases glucose tolerance in healthy volunteers. Cell Metab 33: 957–970, 2021. doi: 10.1016/j.cmet.2021.02.017.
3. Hawley JA, Bishop DJ. High-intensity exercise training — too much of a good thing? Nat Rev Endocrinol 17: 385–386, 2021. doi: 10.1038/s41574-021-00500-6.
4. Holloszy JO. Biochemical adaptations in muscle: Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle. J Biol Chem 242: 2278–2282, 1967.
5. Holloszy JO. Regulation of mitochondrial biogenesis and GLUT4 expression by exercise. Compr Physiol 1: 921–940, 2011.
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