While trawling the web for a spectrum of opinions about the role of hormones in producing the effects of training, I came across a website with the title ‘boost-your-low-testosterone.com’ . The name of the site suggests dedication to the more fragile aspects of the male ego. This impression was re-enforced by the proclamation: ‘A picture is worth a thousand words, so I’m going to show you two right now. First, take a look at this Olympic sprinter…’ [accompanied by a picture of a British sprinter who reminds me of a bison.] ‘Now, compare him with this Olympic marathon runner….’ [accompanied a picture of a Finnish marathoner with slender gazelle-like legs]. The author of the web-page asks rhetorically ‘Need I say more?’
I suspect that my response to the implied question about which of the two physiques is more appealing differs from that of Mark Wilson, the web-page author. Nonetheless, the site raises a very interesting issue. Despite the pop-up adverts for testosterone boosting supplements, Wilson’s message is that exercise in the best way to achieve the desired physique, and his preferred approach is High Intensity Interval Training. Wilson claims: ‘High intensity exercises are so good at reducing fat, building muscle, and increasing testosterone levels, that every male on planet earth should be doing them.’
High Intensity Interval Training (HIIT)
I have for some time been fascinated by HIIT, not because of the claims that it builds muscle (or even on account of its potential for increasing testosterone), but on account of the evidence that it increases aerobic fitness. In fact, there is evidence suggesting that HIIT is more effective in increasing aerobic fitness than in producing muscle hypertrophy. In a series of experiments, Martin Gibala and colleagues at McMaster University in Ontario, Canada, have shown that low volume sprint interval training produces increases in muscle oxidative capacity similar to that produced by much higher volumes of conventional endurance training [2,3].
For example, in one of the studies , ten healthy young men and 10 healthy young women were randomly assigned to either sprint interval training (HIIT) or conventional endurance training for a period of 6 weeks. The HIIT consisted of four to six repetitions of 30 seconds of all-out sprinting on a cycle ergometer with a mean power output of around 500 watts, and 4.5 min of recovery between effort epochs, 3 times per week. The endurance training consisted of 40 to 60 minutes of continuous cycling at 65% of VO2max (mean power output of 150 watts) 5 days per week. Training volume was 225 kJoules per week for HIIT and 2250 kJoules per week for endurance training. Muscle biopsy revealed that both training protocols produced significant but similar increases in the mitochondrial enzymes responsible for oxidation of carbohydrate and of fats. Thus, despite the 10-fold difference in training volume, HIIT produced similar metabolic adaptations to those produced by endurance training. How can this be?
The molecular mechanisms of training
Muscle is one of the most adaptable of human tissues and the past decade has seen spectacular increase in our knowledge about the physiological mechanisms by which training can improve muscle performance. One might hope that this explosion of knowledge would provide rational answers to questions such as: why does HIIT increase aerobic capacity; what is the best training regime to maximize my performance in the marathon, or alternatively, in a 100 metre race; or even narcissistic questions such as how can I look ‘cut’ (which I think means looking like a heroic figure from a Michelangelo painting); or pragmatic questions such as how can I ensure I am still mobile when I am ninety. But the reality is that despite a wealth of knowledge about mechanisms by which muscles respond to training, maximizing muscle performance is still an art as much as a science. Nonetheless, it would be foolish to ignore the science because with current knowledge, the science can make a useful contribution and the best approach is almost certainly to integrate the art with the science.
There are two main classes of mechanism by which muscle performance can be improved: on the one hand, hypertrophy – which is probably important for maximizing 100m performance; is definitely essential if you want to look like a heroic figure from a Michelangelo painting, and might also help you remain mobile at age ninety; and on the other hand, an increase in oxidative capacity, which is crucial for running any distance from 800m to a marathon and beyond. Current knowledge of muscle physiology provides useful guidance about the optimum strategies for producing either hypertrophy or oxidative capacity, though the question of how to optimize both simultaneously remains a vexed question.
The key scientific information is knowledge about mechanisms of cell signaling: the mechanisms by which ‘signals’ initiated by chemical changes such as depletion of the high-energy molecule ATP, or physical effects such as stretching of a muscle, lead to a cascade of chemical reactions that ultimately result in expressing the information coded in our DNA so as to produce proteins that enhance the function of our muscles. Different types of training produce different signals which in turn produce different adaptations in muscle. In particular, some signals lead to enhanced production of the proteins such as actin and myosin that form the contractile machinery of muscle cells. These signals produce increase in strength and muscle diameter. Other signals lead to enhanced production of the enzymes responsible for energy metabolism; in particular, the group of enzymes within mitochondria that form the cytochrome oxidase complex, responsible for oxidation of carbohydrates and fats.
Some of us might be endowed with a genetic message that codes for proteins that perform their role more efficiently, and that might determine whether or not we become an Olympian or a recreational athlete, but whatever the fine details of the genetic message, our goal is to maximize our performance by adjusting our training schedule to optimize the expression of our own genetic information to produce the proteins that govern muscle performance.
The AMPK – PKB switch
In a key set of experiments in isolated animal muscles, John Atherton and colleagues from Nottingham University demonstrated that stimulation by prolonged low-frequency bursts of electrical stimuli, intended to mimic endurance training, activated signaling pathways associated with development of mitochondrial oxidative capacity, while short, high frequency bursts, to mimic resistance training, activated signaling pathways associated with muscle hypertrophy .
[A note about signaling jargon: Unfortunately the full names of the molecules in the signaling pathways are long, complex and utterly meaningless unless you have a detailed knowledge of biochemistry. For convenience, scientists invent names based on the initial letters of the full chemical names – sometime producing whimsical but memorable labels like FOX but in other instance producing strings of initials that are incomprehensible jargon. Fortunately, the tags assigned to the more important signaling molecules eventually become familiar and can be meaningful even without knowledge of the full name. The initial signaling molecule in the mitochondrial oxidative pathway studied by Atherton is adenosine mono-phosphate (AMP) – a close relative of the high-energy molecule adenosine tri-phosphate (ATP). The first step in the signaling pathway involves adding a phosphate group. Enzymes that add phosphate groups are called kinases, so the name given to the signaling pathway the leads to increased mitochondrial oxidative capacity in the AMPK pathway, where the K refers to kinase. Similarly the first step in the pathway that leads to muscle hypertophy is the addition of a phosphate group to a protein, carried out by an enzyme known as protein kinase B, so that signaling pathway is known as the PKB pathway.]
The observation that stimulation of the muscles mimicking endurance training led to increased mitochondrial oxidative capacity while stimulation mimicking resistance training resulted in increased signaling in the pathway to hypertrophy led Atherton and colleagues to hypothesize that the response of a muscle to exercise is determined by an ‘AMPK –PKB’ switch that determines whether or not the adaptation will be mainly increased oxidative capacity or hypertrophy. This hypothesis would suggest that marathon runners have skinny legs because conventional endurance training throws the switch to activate the AMPK pathway. Broadly speaking, the evidence supports this notion, though as we shall see, the picture is more complex.
The molecular mechanism of HIIT
A key player in the cascade of reactions that leads to increased mitochondrial oxidative capacity is a protein with the memory-boggling name: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (abbreviated to PGC-1a). This can be activated by a number of different signals including the AMPK pathway. Giballa and colleagues have demonstrated that HIIT activates AMPK signaling leading to an increase in the expression of PGC-1a in human skeletal muscle [5,6]. Thus, there is fairly clear evidence HIIT is an effective way to increase the oxidative capacity of muscle, and the signaling pathway has a crucial overlap with the signaling pathway involved in more conventional forms of endurance training.
As the evidence for the molecular mechanism of HIIT has emerged, it has become clear that it is potentially sensible for a marathon runner to include HIIT within his or her training program. Of course one might say that Lydiard or Hudson reached similar conclusions without the need for complex science. However, it seems to me that it is only by a combination of practical observation of what works, together with an understanding of the mechanism of why it works, that we will be able to make a rational choice between the competing claims of advocates of various different approaches to training. As for the claim on the ‘boost-your-low-testosterone.com’ website that ‘High intensity exercises are so good at reducing fat, building muscle, and increasing testosterone levels, that every male on planet earth should be doing them.’, the evidence from the studies by Gibala does not disprove this claim, but it does suggest that one of the major consequences of HIIT is switching on the signaling path that leads to increased aerobic capacity, similar to the outcome of endurance training programs that produce skinny-legged marathon runners. If my only goal was muscle hypertrophy, I would place more emphasis on weight training than on HIIT. On the other hand, if my goal is to produce strong but skinny legs, I would definitely include HIIT in the program.
But other things have to be considered
The studies by Martin Gibala and his colleagues suggest that HIIT might be the most time-efficient way to improve aerobic capacity, but despite being a crucial goal of training for distance running, improved aerobic capacity is not the only goal. For the long distance runner, even more crucial is the need to develop resistance against fatigue. HIIT is likely to produce its greatest effects on type 2A (aerobic fast twitch fibres) but these are less fatigu- resistant than type 1 (slow twitch fibres). It is likely that type 1 fibres can be developed more effectively by more sustained less intense training. Nonetheless, for distance extending from 400m to the marathon, peak performances requires highly developed type 2A fibres as well as type 1 fibres, and it is worthwhile devoting at a portion of one’s training program to developing the type 2A fibres.
Among many other requirements is the need to develop the strength and resilience of muscles and other connective tissues, to avoid injury. There is indeed reason to believe that HIIT might also help develop these capacities. If HIIT takes a form similar to the wind sprints advocated by Arthur Lydiard, or the short hill sprints as advocated by Brad Hudson, it is likely to be effective not only in enhancing aerobic capacity but also in developing the strength and resilience of connective tissues necessary to minimize risk of injury, and also in developing good neuromuscular coordination.
The studies of Gibala do not address the question of how HIIT might be integrated into a higher volume training program. Lydiard included wind sprints in sessions that also included long hills, but my own experience suggest that this detracts from the ability to exert full effort during the sprint, and it is possible that the increased level of stress hormones such as cortisol might impede the anabolic benefits of the HIIT. I am more inclined towards Brad Hudson’s approach. He recommends performing short hill sprints on easy days
Signaling via Nur77
Also important is the ability to utilize fats while conserving glucose. It is probable that another signaling mechanism involving the nuclear hormone receptor, nur77, plays an important role in this. Nur77 regulates the expression of genes involved in lipid metabolism and in the storage, release and transport of glucose into cells. Nur77 signaling is activated by exercise and other stressors. A recent study by Lewis and colleagues from Harvard University  has demonstrated that fit athletes can be distinguished from less fit athletes on the basis of blood levels of various metabolites that interact with nur77. It is probably that high levels signaling via nur77 result in efficient mobilization of lipids.
Nur77 also plays a key role in the processes of inflammation. As mentioned in my recent posts, acute inflammation appears to play a role in mediating the beneficial effects of training, but chronic inflammation may be a key factor in over-training and possibly also in long term tissue damage, leading to muscle wasting and perhaps to heart damage. I will return to consider this important issue in more detail in the near future.
Recent advances in understanding cell signaling open up the vista of a world in which it might be possible to plan training programs that optimize the chance of achieving specific goals taking account of both our individual circumstances and our genetic make-up. However the complexity of the emerging picture makes it clear that for the time being, training remains an art as much as a science. Nonetheless what we do know of the science is enough to allow us to understand why different training programs produce different results, and also provides some clues as to how a training program might be tailored to meet the specific needs of an individual athlete. In particular, the evidence suggests that inclusion of HIIT in a distance runner’s program is likely to result in strong, skinny legs.
 Gibala, M.J., Little, J.P., van Essen, M., Wilkin, G.P., Burgomaster,K.A., Safdar, A., et al. 2006. Short-term sprint interval versus traditional endurance training: similar initial adaptations in human skeletal muscle and exercise performance. J. Physiol. 575: 901–911. doi:10.1113/jphysiol.2006.112094. PMID:16825308.
 Burgomaster, K.A., Howarth, K.R., Phillips, S.M., Rakobowchuk, M., Macdonald, M.J., McGee, S.L., and Gibala, M.J. 2008. Similar metabolic adaptations during exercise after low volume sprint interval and traditional endurance training in humans. J. Physiol. 586: 151–160. doi:10.1113/jphysiol.2007.142109.
 Atherton, P.J., Babraj, J., Smith, K., Singh, J., Rennie, M.J., and Wackerhage, H. 2005. Selective activation of AMPK-PGC-1alpha or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle stimulation. FASEB J. 19: 786–788.
 Gibala, M.J., McGee, S.L., Garnham, A.P., Howlett, K.F., Snow, R.J., and Hargreaves, M. 2009. Brief intense interval exercise activates AMPK and p38 MAPK signaling and increases the expression of PGC-1a in human skeletal muscle. J. Appl. Physiol. 106: 929–934. doi:10.1152/japplphysiol.90880.2008.
 Gibala, M.J., and McGee, S. 2008. Metabolic adaptations to short term high-intensity interval training: a little pain for a lot of gain? Exerc. Sport Sci. Rev. 36: 58–63. doi:10.1097/JES.0b013e318168ec1f. PMID:18362686.
 Lewis GD, Farrel L, Wood MJ et al 2010 Metabolic Signatures of Exercise in Human Plasma Science Translational Medicine, 2 (Issue 33), 33 – 37