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Courtesy of P. Ginter/ESRF
Beamline scientist Theyencheri Narayanan watches at the ESRF movable detector used for small-angle scattering.
Muscle protein study could shape cardiac disease research
by Ashley Cullins
April 12, 2011
Courtesy of V. Lombardi, Florence University/ESRF
The muscle proteibn experiment was performed at the European Synchrotron Radiation Facility in Grenoble, France.
Courtesy of V. Lombardi, Florence University/ESRF
This is the setup of the experiment at the ESRF. A powerful synchrotron X-ray technique was used to observe for the first time at the molecular scale how muscle proteins change form and structure inside an intact and contracting muscle cell.
Using X-ray interference technology at the European Synchrotron Radiation Facility in Grenoble, France, the biophysicists applied an electric pulse to skeletal muscle filaments from frogs.
According to biophysicist Malcolm Irving of King’s College in London and co-author of the study, the goal was to understand the mechanisms that control when a muscle activates from a resting state. “We’ve known for a long time that’s due to calcium,” he said. “What’s not known is how that actually leads to switching on muscle.”
The study was published in the current issue of Proceedings of the National Academy of Sciences of The United States of America.
Previous studies have failed to achieve this level of detail, according to Tom Irving (no relation to Malcolm), a biophysicist at Illinois Institute of Technology. “These guys are exquisite experimentalists,” he said. “They’re the best in the business. Not many people are capable of doing these kinds of experiments.”
A supplementary benefit of this data is its potential to affect cardiac disease research. “More people die from heart disease than anything else,” he said. “That’s where it would have the biggest impact ultimately.”
While Malcolm Irving acknowledges this is a possible outcome, he emphasized that it is a long-term benefit. “That’s a very long way off,” he said. “This type of work is getting fundamental information that we think would be useful for designing and testing drugs. You’d love to find a drug that increases strength without slowing relaxation of the heart. In the long term, this kind of mechanism knowledge is going to help in defining therapies for heart disease.”
Tom Irving agreed, but said developing comprehensive models of muscular function that could be used in cardiac research is an important short-term result. “If you have a mechanical understanding of what these things do, you have predictive power,” he said. “So you have models to predict things we haven’t seen yet. That’s a more direct goal, and that’s going to happen first.”
The study analyzed the role of myosin and actin, muscle filaments that control contraction. The synchrotron technology produces extremely bright, narrow X-ray beams. “We put an isolated muscle cell in the beam, so the beam is narrower than the fiber,” Malcolm Irving said. “We used the X-ray to get information on the changes in structure of myosin and actin when its been activated.”
The relative sliding of myosin and actin creates muscle contraction. Myosin drives contraction by reaching out to actin, binding to it and changing its shape in a way that pulls it along before it lets go, he said.
The scientists looked at structural changes in real time, and found that movement of myosin motors was generated after the actin structure changes, he said. He compared the movement of myosin and actin with that of a railway train and the track. “It’s like we designed a system where the track controls the train, not the motor,” he said. “The question is how does the motor know the track is switched on? What we’ve done, really, is make it more necessary to find an alternate signal pathway that takes the signal from the actin filament to the myosin filament.”
Tom Irving said researchers need to look harder at the connection between proteins. "The provocative findings are the things they can’t explain. There needs to be something telling them to contract," he said.
Malcolm Irving said finding these answers is key. “What is the structure of the signal that goes from the actin to myosin and how does it get there?” he asked. “We really don’t know what the mechanism would be. We suspect it might involve other proteins.”
Both myosin and actin have other proteins associated with them, and it’s possible those other proteins are acting as a cross-link moderated by calcium, Malcolm Irving said.
A spinoff from the kinetic results was new information about the configuration of resting myosin motors. The motors seem to be switched off by being packed into an array on the surface of the filaments, according to Malcolm Irving. “What we found is keeping muscles in a relaxed state is achieved by that packing,” he said. “What we now need to know is what controls that packing, what regulates that process.”
Tom Irving said the data is extremely useful, but the study’s interpretation of the data will have to stand the test of time. “It’s a pretty novel idea, and it’s important that we look for this,” he said.
He also stressed the importance of fundamental research such as this study. “You need a model that’s based on real mechanisms. The basic understanding tells you where to look, which things have the biggest effect,” he said. “It’s a challenge to the modeling community. It goes back to overall things, a mechanistic understanding of what goes on. Once you have that, you have predictive power. Then it can become clinically useful.”
According to Malcolm Irving, two primary findings will drive future research: myosin motors are packed down in the switched-off structure and the relative speed in the steps involved in activation. “Now we need to look for the molecular pathway that links the structural change in actin to structural change in myosin,” he said. “Those are the next steps.”
