The human machine: different models

The previous post in this series can be found here.

You may have noticed, but we're holding a little sporting shindig here in London over the next two weeks that's got everyone rather excited. I myself am going to be spending a lot of time shuttling back and forth between the Olympic park and my house in Oxford and most of the rest of the time glued to my laptop watching as many sports as is humanly possible! Thanks to this busy sporting schedule, this week's post will be somewhat shorter than some of my others in the past, but I hope you still find it interesting. You may think, dear reader, that I will be shirking my scientific duties by devoting myself so fully to the Olympic smorgasbord but my enthusiasm is born out of pure biochemical curiosity and the sporting element is, I can assure you, wholly secondary! 

How does biochemistry fit into the greatest show on Earth, you may ask? How does it not, I would respond! All of the athletes competing in this year's games have spend years training to improve their body's biochemical response to stress and physical exertion in order to fulfil the Olympic ideal of 'faster, higher, stronger'. In my last post of this series I described the molecular processes that allow muscle contraction and in the preceding post I talked about how energy is processed within your cells to produce the 'energy currency' of your post: ATP.  In this post I will bring these two topics together and discuss how energy is regulated in different muscle types and how the biochemical situation varies hugely between the 100m and the marathon.

Getting out of the blocks

Imagine a resting muscle cell, plenty of ATP available and no contraction using it up. Suddenly, the gun sounds - the athlete waiting in the blocks calls on every cell in his muscle to contract furiously to propel him forward towards the finish line and to the glory of gold! In the first second or so the power stroke that drives muscle contraction (see my last post for the beautiful details) is still adequately supplied by the stores of ATP that were hanging around in the cell, but these won't last long. As these begin to wane the cell turns to another vital store of energy that it holds in reserve for just such an eventuality: creatine phosphate.  As you may recall from the first post of this series, when ATP is used up it is split into ADP and inorganic phosphate. As the name suggests, creatine phosphate also contains a phosphate group and is able to donate this directly to ADP, thereby reforming ATP that can be used again in yet more muscle contraction and leaving behind a spent creatine molecule. This recharging system extends the lifetime of this initial store of ATP to about 7 seconds of full contraction, almost enough to make it to the finish line of the 100m! 

Rechargeable batteries - biochem style!

Indeed, 7 seconds may not quite be enough for Usain Bolt but it should be plenty for a weightlifter performing a dead lift. This is why many athletes in strength-based sports like weightlifting take creatine supplements in an attempt to boost their intracellular stores of creatine phosphate and give them that extra burst of strength.

Going the distance

What happens next depends heavily on who the athlete is and what they're doing. It goes without saying that a sprinter needs speed but not endurance whereas a marathon runner needs endurance but not speed. Endurance and speed have very different requirements, biochemically speaking. Speed and strength require very rapid contraction and large initial stores of energy that don't need to be replenished. Endurance, on the other hand, necessitates slow, consistent contraction with a regular turnover of ATP where demand never outweighs supply. Achieving both in a single cell is very difficult from a biochemical perspective, so instead we have several types of muscle cell that are individually tailored to different duties.

Bolt, Lewis, Thompson

The types of cell that dominate in the muscles of sprinters are known collectively as type II (or fast twitch) fibres, but actually consist of three distinct subtypes: a, b and x. Type IIb muscle is responsible for super-fast, super-strong contraction and are packed full to bursting with ATP and creatine phosphate. Unfortunately, producing ATP from anything more complicated than creatine phosphate takes too much time to replenish the cellular stores and so contraction in type IIb cells has a very limited lifetime; well under a minute in even highly trained individuals. 

Following on from these 'super-twitch' muscles are the type IIx fibres, a cell type that has only recently been recognised as distinct from the other type II fibres. These are very similar to the IIb fibres but have a limited capacity to extend their contraction lifetime by generating ATP from another source: glycogen. Glycogen is the form in which glucose, the primary sugar used by cells to produce ATP, is stored. As a muscle contracts, numerous biochemical sensors detect falling ATP levels and ramp up the release of glucose from glycogen in a process known as glycogenolysis. This newly liberated glucose is then free to enter a complex series of chemical reactions known as glycolysis, in which glucose is converted to a molecule called pyruvate and produces 2 molecules of ATP, thereby allowing contraction to continue for just that little bit longer. 

Glycolysis: a sprinter's best friend!

If there is plenty of oxygen around, pyruvate enters another process known as the citric acid cycle (more on that later) to squeeze out that extra bit of energy. In a rapidly contracting muscle, however, oxygen simply can't diffuse into the cells fast enough to meet demand and so instead the pyruvate being churned out by glycolysis is converted into lactic acid and pumped into the blood to prevent catastrophic acidification of the  contracting cell. 

The inclusion of glycolysis in type IIx muscle extends the contraction lifetime of this cell type up to around 1-3 minutes, enough for perhaps a short swimming event or 400/800m run. For the slightly longer speed events, type IIa muscle is what's really required. This muscle type relies primarily on glycogen for ATP generation but contracts more slowly than IIx and IIb fibres and so oxygen diffusion into the cells is able to keep up with demand. In order to ensure this, IIa muscle contains a higher density of capillaries to maintain a plentiful blood supply to the contracting cells. This oxygen allows the pyruvate produced by glycolysis to enter the aforementioned citric acid cycle, in which it is chemically converted in several steps to produce oxaloacetate, which then combines with another molecule of pyruvate and starts the cycle all over again. This cycle doesn't produce ATP directly but instead generates NADH, which (as detailed in a previous post) is used by mitochondria to fire up the ATP-production engines that are ATP synthase.  

The central roundabout of all metabolism!

It would seem that this system could continue to pump out ATP indefinitely but unfortunately cells can only store so much glycogen within them and eventually this store runs out. While oxygen is able to diffuse into type IIa cells quickly enough to allow full metabolism of glycogen, fresh glucose is much slower at getting into the cells and so is not able to replenish cellular stores fast enough to allow indefinite contraction. The depletion of cellular glucose can be delayed by things such as carb-loading and sports drinks, but it is, sadly, inevitable - usually occurring within half an hour for strenuous exercise or 2-3 hours for more moderate work. Nonetheless, you can do a lot in that time - as I'm sure any 10km runner will tell you!

Gebrselassie, Radcliffe, Felce

In order to keep going for longer, an entirely different cell type is needed. Professional marathon runners do have a fair stock of type IIa muscle that is required to reach the kind of speeds they go at,  but the majority of their contraction takes place in what are known as type I (or slow twitch) muscle fibres. These muscles are packed full of blood capillaries and mitochondria to allow a consistent slow rate of contraction over many, many hours. In fact, this muscle type is able to continue contracting indefinitely because there is a perfect balance between the supply of fuel and its use. If this weren't the case we would all be in trouble, because the heart is an almost entirely slow-twitch muscle and if it were unable to continue indefinitely we would soon know about it! 

The reason why type I muscle can theoretically continue forever is that it uses ATP slowly enough for it to be replenished through the metabolism of triglycerides, known better to most people as fat. Fat is stored in cells called adipocytes and is released into the bloodstream when blood triglyceride levels drop during exercise, which is why exercise means you lose weight. The surface of type I muscle cells are covered in fat transporters that latch onto triglycerides and move them into the cells for metabolism. Once inside the cell, triglycerides undergo a process known as beta-oxidation, which produces acetyl CoA, another molecule that enters the citric acid cycle and so pumps out NADH to keep the cell's mitochondrial machinery turning. Doing low-intensity, high-endurance exercise is the best way to shift unwanted fat because of the relentless consumption of triglycerides by type I muscle: weightlifting and sprinting will, I'm sorry to say, not help you in that regard!

Playing the hand you're given

No-one is formed of entirely type I or entirely type II muscle, but there is a huge genetic variability between individuals and races. East African men have dominated long-distance running for a century primarily because of their predisposition for high type I percentage muscles, whereas men of west African ancestry tend to be more genetically inclined towards type II muscle, making them better sprinters. The difference in physiology is immediately apparent between the two types of athletes, with distance runners having the small but efficient type I muscles, whilst sprinters have the large but easily fatigued type II muscles.

Usain Bolt vs Haile Gebrselassie - spot the difference

Unfortunately for some, it is difficult to change your type I/II muscle composition through training, you just have to work with what you've got. A natural sprinter training for a long-distance race will improve his type I capacity but will have to make some gains in his type II to achieve it, which limits to degree to which he can focus on distance. The converse is true for an endurace athlete trying to train for a sprint.

Understanding the way that different muscle types respond to training is a hugely lucrative area of biomedical research given its obvious implications for the wealthy world of professional sport, but also for more therapeutic applications such as in recuperative physiotherapy. We are slowly beginning to understand the signalling networks that detect exertion in muscles and promote additional growth and/or adaptation towards efficiency. What has been emerging from recent work is that there are 5 or 6 triggers for growth that include oxygen depletion, neuronal firing, mechanical contraction, and metabolic markers, with different training styles triggering different responses. Anaerobic training, such as sprint repetitions or weightlifting, will evoke responses from the detection systems for oxygen depletion or lactate accumulation; whereas endurance training will promote detection of mechanical contraction or neuronal firing. Each detection system regulates the expression of different genes and so promotes the growth of different muscle types, with any given exercise sitting somewhere on the spectrum between fully anaerobic to full endurance. 

This area of research is still uncovering unexpected regulation in the way muscles develop and adapt to training, which is likely to lead to more sophisticated training regimes and nutrition in the future. Spare a thought for the athletes in London this week - they were born just too early to benefit from the work being done now! Thanks to our ever-improving biochemical understanding, 'faster, higher, stronger' may well be feasible for some time to come.

The next post in this series can be found here.