A marathon - 42 195 metres of biochemistry

A marathon is a hard test of the molecular motor of the human body. Here we can follow the author’s and runner’s path from start to finish.

Paris really did not show its best side, but despite the cold and raw weather, the air vibrated with the heat from the 35 000 runners who stood waiting. It was early morning on 10 April 2005 and I was about to run my first marathon. We often take our bodies for granted, but during a marathon everything is pushed to the limit, so put on your running shoes and join me on a long and at times really rather torturous journey through the fascinating world of biochemistry.

I was naturally a little nervous ahead of more than 40 km of running and my body responded by releasing adrenaline from the adrenal gland. Adrenaline is a hormone that prepares the body for flight by increasing the blood flow to the heart at the same time as increasing the release of glucose from the body’s store of glycogen.

The adrenaline makes it easy to run, but it is not tactical to use up the body’s easily accessible, precious energy too early on in the race.
Most biological processes are powered by a molecule called adenosine triphosphate, often abbreviated to ATP. Because adenosine triphosphate is constantly being formed and broken down, the body uses more than its own weight in ATP every day.

In order for us to be able to move, our muscles must be able to contract, which, chemically, is quite a complicated process. The muscles are made up of muscle fibres, which are polynuclear, long cells. The muscle cells contain ‘muscle fibrils’, which in turn are made up of a number of different proteins, the two most important of which are actin and myosin.

When the starting gun goes off, the brain sends a signal to the skeletal muscles in the legs and releases calcium ions which make the myosin bond to the actin. Myosin is charged with an ATP molecule and when it bonds to actin the energy is released and the front part of the myosin is angled, which spreads as a movement in the muscle cell.

If there is sufficient energy, a new ATP molecule is bonded to myosin and the procedure is repeated. The process can be likened to a gear rack. If there is enough ATP then we can keep running for a very long time.

On the other hand, if the amount of ATP falls, the muscles have more difficulty working and our legs become heavy. When we die, the production of ATP ceases entirely and the muscles remain in their contracted state, which is usually known as rigor mortis.

When we start running, the ATP that is found in free form in the muscle is used first. In addition, there is a store of creatine phosphate, a molecule that can be converted into ATP very rapidly. In total we have around two grams of these molecules, which provides 5 kcal of energy. Our store of ATP and creatine phosphate lasts for around ten seconds, which corresponds to the first 80 metres of the marathon.

In actual fact we have quite a lot of energy in the body, but it is almost all stored in the form of carbohydrates, fat and protein. Most of the carbohydrates in the body are bound in the form of glycogen, a macromolecule with up to 30 000 units of glucose. When the ATP and creatine phosphate have run out, the body therefore starts to burn glucose that is released from the glycogen. The problem is that it takes around two minutes for the heart and lungs to reach their full capacity and the oxygen is not sufficient to effectively use glucose until this point. Instead the body resorts to a type of emergency function known as anaerobic metabolism, in which glucose is broken down to lactic acid. For every glucose molecule, two ATP are immediately released.

So, lactic acid provides quick energy, but as soon as we have got our breath the body goes over to the more effective aerobic metabolism, which releases 36 ATP per unit of glucose. During a normal run, however, the body will make use of both types of metabolism. Sometimes, perhaps when going uphill, there is not enough oxygen and then lactic acid is formed instead.

Once the body has adapted its breathing to the running, lactic acid will quite quickly be converted into energy and studies using radioactive-labelled substances have shown that it is actually broken down more quickly than glucose, as long as there is plenty of oxygen. The lactic acid also curbs the normal metabolism, which means that it works as a sort of brake so that we don’t wear ourselves out too much. The fact that anaerobic metabolism is less effective than aerobic can be seen in elite runners’ marathon times, as they often run faster in the second half of the race than the first. In the 2011 Boston Marathon, Kenyan Geoffrey Mutai won in the incredibly impressive time of 2.03.02. His time for the first half was 1.01.58, whereas the second half was almost a minute quicker at 1.01.04.

For many years it was believed to be lactic acid that caused sore muscles after exercising and this misperception was largely based on a series of experiments carried out by Nobel Prize winner Otto Meyerhof in the early 20th century. When electricity is passed through frogs’ thighs, the muscles contract and it is possible to make the leg move – despite the fact that the frog is dead. Meyerhof observed that the frogs’ thighs could only be made to move a handful of times and he discovered that large quantities of lactic acid were formed. He interpreted this to mean that lactic acid caused muscle fatigue. It was not until the 1970s that researchers discovered that this was not really true – an hour after a run there is no lactic acid left in the muscles.

Muscle soreness after exercise, or delayed onset muscle soreness, as it is officially known, usually increases in intensity, reaching a peak after one or two days. We still don’t know exactly how the pain comes about, but studies from Umeå University show that it is related to the building up of muscle rather than an inflammatory response to muscle injury.

Muscle soreness primarily occurs when the muscles have to work in resistance movements, i.e. without being able to contract. This is why the pain becomes worse when we run downhill than when we run uphill. When we get exhausted, it is difficult to avoid movements that cause muscle soreness and most marathon runners experience strong muscle pain. The day after the race, Paris was full of people with tender thigh muscles going backwards down the stairs.

A few minutes after the start, my aerobic metabolism was fully functioning and over the coming kilometres, mainly through the Bois de Vincennes, I trotted along at an average pace of five minutes a kilometre. Just after half way through the race I was positively flying along on what is known as a ‘runner’s high’ – the endorphins had kicked in.

In 1975, two research groups published articles independently of one another on substances produced by the body that appear to have an opium-like, pain-relieving effect. Because they were formed in the body, they were named endorphins (endogenous morphine). As well as pain, endorphins appear to play an important role in laughter, sex and physical exercise, and just like with morphine, we can become addicted to endorphins. An exercise addict is addicted to the endorphin kick after an intensive training session. After 45 minutes of hard running, the body secretes endorphins equivalent to 10 milligrams of morphine – a normal pain-relieving dose.

Unfortunately, my endorphin rush did not last long. Despite eating sugar at every station during the race, the famous ‘wall’ came after almost exactly 30 km. Normally, we have around 400 g of glycogen in our skeletal muscles and an additional 100 g in the liver. Because most people use 60–65 kcal to run one kilometre, the body’s glycogen, which is the equivalent of 2000 kcal, will last for just over 30 km of running. When the glycogen runs out, the body has to go over to other sources of energy. We have around 7–8 kg of protein in the body, which is the equivalent of 30 000 kcal. This is enough energy to run almost 500 km, but the problem is that all the proteins in the body are functional and the body therefore prefers not to use protein as a source of energy. In a long-distance race, around five per cent of the energy used nonetheless comes from the breaking down of protein.

It is instead fat that becomes the most important energy source. I have around 8–9 kg of fat, which is the equivalent of 80 000 kcal, enough energy to run from Malmö to Skellefteå in northern Sweden. So it can’t be all that difficult to jog round Paris for a bit, can it? Unfortunately, only a small amount of the fat, around 300 g, is interspersed in the muscles and therefore easily accessible for the body during a marathon. Despite the fact that fat actually provides most energy per unit of weight, a lot of oxygen is required to convert it into energy and when there is not enough oxygen, the ATP levels sink dramatically and the runner’s legs become like lead weights.

One way to avoid this is to load up with carbohydrates. With a well thought-out diet it is in fact possible to almost double the amount of glycogen in the muscles. At the same time, 2kg of water is also bound in, which is very useful during the actual race. A loss of fluids is namely another reason why it is difficult towards the end of a marathon. As soon as the temperature of the skin rises above 37°C we begin to sweat, because sweating is a very effective way to cool down. We can lose several litres of fluid every hour, fluid which must be replaced if we are not to risk getting heatstroke.

However, it is not entirely obvious what one should drink to replace the lost fluid. Plain water is clearly the best alternative for shorter runs, but because water does not have a lot of flavour, most people find it difficult to drink sufficient amounts to replace the fluid lost. When we sweat we also lose quite a lot of salt, and during a long run it is best to drink some type of sports drink that contains both salt and sugar. Sports drinks usually contain six to eight per cent carbohydrates and also have a sour taste that makes it easy to drink a lot.

However, it is best to avoid fruit juice during a marathon because it contains a lot of fructose. The problem with fructose is that we have a limited capacity to absorb it in the small intestine. The fructose that is not absorbed is transported to the large intestine, where it reduces water absorption, which causes diarrhoea, and converts bacteria to various kinds of gases, primarily carbon dioxide, methane and hydrogen. Around 40 per cent of the population of Western countries also have a reduced capacity to absorb fructose, similar to lactose intolerance, which causes very difficult stomach problems.

My glycogen ran out just by the Eiffel Tower. It was almost unreal. Right out of the blue my legs turned to lead. It was no longer about running, but rather about simply overcoming the pain from my legs, and the final 12 kilometres were excruciating, with an average speed of over six minutes per kilometre. After 3 hours 47 minutes and 54 seconds I stumbled across the finishing line. I didn’t know biochemistry could be so painful!

Joule or calorie?

The SI unit for energy is the joule (J). Despite that, the unit most often used for the nutritional content of food and consequently the energy needed for different kinds of physical activity is the calorie (cal). In everyday speech, the word calorie is often used incorrectly to mean kilocalorie (kcal).
1 kcal = 4.18 kJ

• ATP. The body uses more than its own weight in adenosine triphosphate every day.
• Carbohydrate loading almost doubles the amount of glycogen in the muscles.
• A runner can lose several litres of fluid an hour.
• Around 60 kcal are needed to run one kilometre.

- By Ulf Ellervik, Professor of Bioorganic Chemistry, Lund University