Muscles activated by mechanical force (9/5/2008)

Dr Mathias Gautel, Professor of Molecular Cardiology from the Randall Division for Cell and Molecular Biophysics and his team from the Cardiovascular Division at King's, have shown for the first time, how muscle can be regulated by mechanical force, a finding that is likely to be typical for other biological systems.

In a paper now published in the journal Proceedings of the National Academy of Sciences, the team proved their long suspected theory that the giant protein titin, an elastic connection holding the muscles contractile machinery together, contains a signalling domain that can be switched on mechanically.

Dr Gautel comments: 'The proof that mechanical activity can directly activate the titin kinase domain is exciting because it provides unique insight into a completely novel paradigm for signal transduction. It will now allow us to understand the way titin regulates the growth and shrinking of muscles in normal and disease states much better, and may ultimately offer new approaches for intervening in muscle diseases.'

The research will help towards the understanding of conditions which involve loss of muscle mass, such as Edstrĝm's Myopathy, a lethal muscle disease where a mutation in the titin kinase domain interrupts crucial signals that control muscle mass. Other conditions where muscle mass is lost, or excessively added under changes of mechanical activity are likely to involve the same titin-based mechanism.

The work, funded by the Medical Research Council European Union and Centre for Integrated Protein Science in Munich, was a collaborative project between Prof. Gautel's team and the teams of Profs. Hermann Gaub and Helmut Grubmüller, at the Ludwig-Maximilians-University Munich, and the Max-Planck-Institute for biophysical Chemistry in Göttingen, Germany.

Molecular mechanism

Using a combination of biochemistry and enzymatic studies, single molecule experiments and complex computer simulations, they could unravel the molecular mechanism revealing how mechanical force can open the tightly regulated titin kinase domain, allowing it to bind its substrates and signal to other proteins.

With the protein from King's, Elias Pucher from the Munich team was able to show how the mechanical properties of single titin kinase molecules changed when they bound substrates. This property was mechanically triggered, as also the enzymatic studies at King's showed.

Computer simulations of the mechanical activation by the Göttingen team unravelled the molecular pathway, allowing the designed intervention in further experiments to corroborate the simulations. The simulations also predicted the enzyme to modify itself upon mechanical activation, which again could be proven in biochemical experiments by Ay Lin Kho and Alexander Alexandrovich from the King's team. The results of the three groups are thus highly complementary.

Dr Gautel explains: 'This is the first demonstration of how signalling in muscle can be directly modulated by mechanical activity, a mechanism relevant for understanding the growth and shrinking of muscle in response to changes in activity.

'Many similarly operating cellular systems are likely to exist, suggesting that the study of titin will be paradigmatic for understanding mechanosignalling in other cell types. Our next steps will be to analyse the effects of mechanical activity on titin kinase signalling in models of heart and skeletal disease.'

This research is part of the work being undertaken within the King's British Heart Foundation (BHF) Centre of Excellence, recently established with £9 million funding from the BHF with the aim of promoting cutting edge research and training in cardiovascular research.

Note: This story has been adapted from a news release issued by the King's College London

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