Human muscle cells can adapt their metabolism for maximum performance. This is done by a switch from oxidation of glucose into carbon dioxide and turning glucose into lactic acid. Researchers at Chalmers have found that a previously unknown mechanism, the bypass of the enzyme Complex I, also contributes to enhancing cell capacity.
ATP are the high-energy molecules cells get from glucose oxidation. ATP is used by enzymes to build biomass and perform other energy demanding tasks in the cell, such as movement in muscle cells, transport of signal substances in braincells, enhance light signals in the retina and degradation of damaged cell parts. If the ATP amounts are too low, the cells cannot function properly.
Muscle cells cannot store large amounts of ATP, they must produce the molecules at the same rate as they are used. There is a trade-off between maximum efficiency (amount ATP/glucose molecule) and maximum capacity (amount ATP/time unit/gram biomass) in the cells. When exercising at high intensity the cells will turn glucose into lactate, lactic acid, which is less efficient – but results in a faster production of ATP.
Study shows how enzyme capacity affects ATP-production
But there are other aspects that affects the cells efficiency. In a study recently published in Nature Communications, Avlant Nilsson, postdoc at the Massachusetts Institute of Technology and former PhD at the Department of Biology and Biological Engineering, has along with guest researcher Elias Björnson, developed a computer model of a muscle cell to study how limited catalytic capacity of enzymes affects ATP synthesis. The model compiled information on all enzymes in the synthesis pathway.
Bypass increases ATP-production
"Our computer simulations of metabolism take both measured enzyme levels and their catalytic capacity into account. They identify several bottle necks in ATP production, one of which is Complex I. In the simulations the enzyme is bypassed after reaching its max capacity. This increases the rate of ATP production, but at the cost of reduced efficiency, the expenditure of both glucose and oxygen per ATP increases after the bypass,” says Avlant Nilsson, first author of the study.
In vivo-tests confirmed the results
To examine if the bypass shown in the computer simulation also takes place in vivo, in this case in human muscles, researchers at The Swedish School of Sport and Health Sciences in Stockholm, Sweden, were involved. They conducted tests under different conditions with five subjects.
The hypothesis was that the bypass happens at high intensity exercise. If correct the researchers expected to observe lower efficiency, that in a graph plotting oxygen consumption rate against exercise intensity, the slope would be steeper at high intensities. The hypothesis matched the test performed on the five test subjects.
Bypassing Complex I increases the rate of oxygen and glucose consumption in the cells. This type of biological insight may be useful for professional athletes that need to be economic with their nutrient reserves during endurance sports such as marathon. It also implies that current methods to estimate ATP production rates from oxygen consumption rates may exaggerate the estimated ATP production.
Results might be relevant to cancer and brain research
“Since such measurements are routinely performed in both cancer and brain research, this phenomenon would be of great interest if it turns out that it occurs also in other cell types,” says Avlant Nilsson.
Complex I is interesting due to its contribution to obtaining more ATP from every glucose molecule, which is good from an efficiency point of view. At the same time the enzyme is large and slow, which is impractical when there is a need for a fast ATP production.
Some fast-growing organisms, for example baker’s yeast, have lost the ability to express the enzyme. Avlant Nilsson’s model shows that when more ATP is needed the enzyme is bypassed, and the metabolism is redirected during high intensity exercise.
Contributes to a detailed understanding of the metabolism
“This type of computer simulations helps us to better understand cause and effect in cells. A detailed understanding of metabolism can be informative for measuring the effects of a training regime.” Says Avlant Nilsson. He continues:
“Simulations are also useful in many other situations, e.g. to better understand growth of cancer cells. Similarly, to highly active muscle cells, many cancer cells also produce lactate. It is possible that future research will show that some of them also bypass Complex I.”