The heart is a special organ; not only is it a muscle that works continuously, but it can also vary its power output enormously. During sleep and in a hundred metre sprint the heart can – nearly always – take it. Of course this wide performance range goes hand in hand with a variable energy consumption, which is easily recognisable e.g. by the breathing rate. However, if one now looks into a muscle or heart cell, one is confronted with a paradox: the concentration of the cellular energy unit, ATP, remains highly constant over a wide range of power output from the heart.

So what does this mean? Is the cell able to synthesise ATP so fast that it can follow the variable energy consumption? Or are there some other storage molecules? Which molecules might come into question as candidates to convey the energy demands so quickly? A whole complex of questions that, among others, ETH professor Theo Wallimann and his colleague Uwe Schlattner at the Institute of Cell Biology have been working on for a long time (1). Together with research colleagues from France and the USA, they recently presented one model of the relationships in a review article in the scientific journal “The Journal of Physiology” (2).

The cell is not just a sackful of enzymes

In reply to the last of these questions, namely what is the fast messenger, one answer appears frequently in the literature: calcium. This substance is certainly relevant, since muscle contraction depends directly on it. In addition it can be controlled very precisely. Nevertheless, according to Wallimann, calcium on its own cannot regulate heart muscle activity. This is because the loading demands on the heart vary by a factor of 20, whereas the corresponding calcium concentration differences cannot initiate the required energy flows. Furthermore, the ATP consumption can be doubled without a change in the concentration of calcium.

So how do ETH researchers cope with these contradictions? “The inconsistencies are based on a viewpoint that is too simple,” explains Wallimann. They arise when the cell is regarded as a bag without any internal structure, in which the exchange of metabolites and signal molecules takes place merely by passive mixing like in a soup. However, this long-standing dogma is increasingly unable to hold out against recent research results. Wallimann in Professor Hans Eppenberger’s group at ETH already showed in the seventies that various forms of the enzyme creatine kinase occur in various sub-cellular compartments. For example there is a specific creatine kinase in the mitochondria, the ATP production sites. This enzyme phosphorylates creatine, i.e. it attaches a phosphate group to the substance, thus making it more energy-rich.

How energy flows in the cell: Energy-rich ATP is produced in the mitochondria (left). This ATP transfers its phosphate group to creatine (Cr), which acts as a fast carrier to transport energy in the form of phospho-creatine (PCr) to the site where it is consumed (right). Creatine is channelled into the muscle cells by a special creatine transporter (CRT) (Graphic: Schlattner and Wallimann from Saks et al. (cf. Footnote 2)). large

Creatine, an exchange currency

Further research, to which Wallimann and Schlattner’s group made a substantial contribution, finally yielded an extended cell energy supply model. ATP still plays an important role in this model, but the rapid energy flow also needs creatine as the “exchange currency”. Thus ATP is actually produced in the mitochondria, but it is not carried directly to the site where it is consumed. Instead it transfers its energy to creatine by means of a phosphate group. The energy-rich phospho-creatine thus formed then transports the energy onwards to where there is an energy demand, where it transfers it in turn to ADP, which contains one phosphate group less than ATP, to regenerate the latter in situ.

The system may sound complicated, but it has advantages. For example the phosphorylated creatine represents a buffer stock of energy. In addition, because it is small, it increases the speed of energy transfer. Because phospho-creatine is metabolically inert, in contrast to ATP and ADP, which interact with a multitude of cellular enzymes and structural proteins, it is particularly suitable for the loss-free transport of energy. These properties, together with the high degree of structuring within the cell, also explain how energy can be provided very quickly, for example in heart muscle cells, while the ATP concentration nevertheless remains constant when considered over the entire cell.

Movement and cellular energy metabolism

Although this gives the researchers a better understanding of how energy supply in the cell is orchestrated, the subject is nowhere near fully exhausted. Wallimann’s group is now increasingly occupied with the role of the enzyme AMP-activated protein kinase (3)(4). This enzyme is involved as an energy sensor in the regulation of the cellular energy metabolism. In particular it registers when an energy stress arises in the cells, whether for example as a result of an oxygen deficiency or because of free radicals. The action of AMPK activates a whole series of cellular metabolic pathways, which among other things increase the uptake of glucose and activate the combustion of fatty acids in order to compensate for an imminent energy deficiency.

The group is carrying out the ongoing research work in the context of the EU project “Exgenesis”, which is investigating the mechanisms underlying the beneficial effects of physical fitness improvement. It is hoped that this will lead to the discovery of new starting points to combat overweight (obesity), Type 2 diabetes and the metabolic syndrome. This is because it is advantageous to know how physical exertion has an effect in the cell on energy consumption and the breakdown of fat in order to enable the increased pulse rate during sporting activity to be utilised purposefully.