CeNS Center for NanoScience LMU Ludwig-Maximilians-Universität München
CeNS HomepageLMU Homepage
Home  >  Research

Molecular Force Sensor Controls Growth of Muscles

Olympians in Peking probably didn’t think about the molecular function and regulation of their muscles during competitions. They must have been much more interested in the question if their training and the growth of their muscles had been ideal. But how does the muscle measure the mechanical stress during training and “notices” when to perform better? This mechanism was now deciphered by an interdisciplinary research team of the Ludwig-Maximilians-University (LMU) Munich and of the Max-Planck-Institute for Biophysical Chemistry in Göttingen in collaboration with the King’s College London (England). In their work, the scientists found out that a protein in the muscle acts as a force sensor. When activated by muscle tension, this protein causes the creation of new muscle proteins in the cell nucleus.

Very few people are able to do several pull-ups in a row at first go. However, with the appropriate training almost every one of us is able to pull itself up. Our muscles grow with the amount of effort we make and they give us the necessary power to do the exercise – in contrast, when doing nothing, we rapidly lose our muscle mass. But how does the muscle know when to grow and when to shrink?

An international scientists’ team now pursued this question. For a long time already, researchers have already been assuming that there must be a kind of power sensor present in the muscle which measures the strain and passes on the information. One specific muscular protein seemed most capable for this task to the scientists: titin – a real giant in the empire of proteins. Together with two more muscle proteins, actin and myosin, it is one of the main components of the sarcomere, which is the smallest force-generating unit of our cardiac and skeletal muscle. While actin and myosin make the muscle move, titin stretches across the sacromer, holding it together like an expander spring and providing for the essential flexibility of the musculature. Through a combination of methods like Atomic Force Microscopy (AFM), computer-based simulations and enzymatics, the scientists were for the first time able to show directly that a special part of the huge titin protein can actually act as a mechanical sensor.

Elias Puchner from the Chair of Prof. Hermann Gaub and member of the International Doctorate Program NanoBioTechnology provided the first experimental evidence that titin kinase, a special chain link within the titin, is activated mechanically. For that purpose he clamped the protein between a surface and an extremely sharp tip of a custom-built AFM. With this method singular proteins are stretched (i.e. unfolded) in the same way as they are in the muscle, making smallest changes during the stretching detectable. In this way, Elias Puchner was able to show that the binding of small ATP-molecules to the binding site of the titin kinase only happens when the titin kinase is mechanically activated through partial unfolding. Crucial in doing so was the discovery that ATP stabilizes the binding site and that it leads to changes in the unfolding profiles (i.e. measured force vs. extension of the titin kinase) that were recorded by the AFM. The measured forces leading to activation are in the physiological range and smaller than the forces needed to stretch the neighbouring titin parts – an essential precondition for a force sensor.

In the next step of the mechanically activated signaling cascade, a phosphate group of the ATP-molecule is separated from the catalytic centre of the titin kinase and fixed to another protein as a marker. The biochemical signal, which is initiated in this way, eventually regulates the production of muscle proteins in the cell nucleus, as proved by the collaboration partners at King’s College.

The scientists around Prof. Helmut Grubmüller at the MPI for biophysical chemistry in Göttingen simulated the experiment to see what happens exactly to the protein under mechanical stress, i.e.  powerful stretching of the muscle. When the protein is now being pulled by a virtual tip of the AFM in the computer simulation, it is possible to witness the protein movement atom by atom. In this process, the part of the protein that had blocked the active centre like a plug opens up. The now accessible active centre is able to cleave the ATP and to trigger the signal chain. In the static condition the titin kinase blocks itself with this plug, preventing the binding of the ATP. Like this, the results of the three groups affirm and complement one another.

Malfunctions of the titin kinase play a key role in some genetic disease of the muscles like the Edstrøm-disease. Presumably caused by these malfunctions, the muscles cannot be regenerated adequately – with fatal consequences for the patients, as the highly stressed breathing musculature collapses first. A better understanding of the molecular interconnections between growth of the muscles and regeneration could thus be of crucial relevance to the development of new pharmaceuticals for the treatment of certain muscles diseases. But also sportive people and top athletes could benefit from the newest findings of the scientists in their trainings.


"Mechanoenzymatics of titin kinase"
E. M. Puchner, A. Alexandrovich, A. L. Kho, U. Hensen, L. V. Schafer, B. Brandmeier, F. Gräter, H. Grubmüller, H. E. Gaub, M. Gautel
PNAS, 105(36):13385-13390 (2008)


3D Animation dieses Forschungsergebnisses (Video)


Source: Translation of the Orignialpressemitteilung von Carmen Rotte, PR Max-Planck-Institut Göttingen

Elias Puchner

* 1981


seit 2010
Postdoctoral research at the
department of Cellular and Molecular Pharmacology,
UC San Francisco

2008 - 2010
Postdoctoral research in the group of Prof. Hermann Gaub, LMU

2006 – 2008
Doctoral Thesis,
Supervisor: Prof. Hermann Gaub, LMU

2000 – 2006
Diploma in physics, LMU Munich

Selected Publication

Kufer S.K., Puchner E.M., Gumpp H., Liedl T., and Gaub H.:
"Single-molecule cut-and-paste surface assembly
Science, 319(5863):594-6 (2008)