X-Rays Provide New Clues into Muscle Contraction Mechanics

An international group of scientists from Italy, the United Kingdom, and France has now brought this classic textbook case into the nanoscience era. They used a powerful new synchrotron X-ray method to track, for the first time, at the molecular scale how muscle proteins change form and structure inside an intact and contracting muscle cell.

The study's findings are published in the April 11, 2011, issue of the journal Proceedings of the [US] National Academy of Sciences (PNAS). The team included scientists from Università di Firenze (Italy), King's College London (UK) and the European Synchrotron Radiation Facility (ESRF; Grenoble (France).

A muscle cell contains two sets of filaments composed of the proteins actin and myosin, respectively. Muscles contract as a result of the relative sliding of these filaments. When the brain sends a nerve signal to activate a muscle, the electrical signal is transmitted to the muscle cell. This initiates a chain of events inside the muscle cell that ultimately leads to alterations in the structure of the myosin and actin filaments.

But what precisely occurs during this process at the molecular level? "As we need muscles for locomotion, breathing and body posture, and for the contraction of the heart, understanding of these mechanisms has broad significance in biology and medicine,” said Dr. Malcolm Irving, from King's College London, and coauthor of the study.

"Studying a single intact and contracting muscle cell at the molecular scale in milliseconds became possible thanks to a new technique called X-ray interferometry based on low angle diffraction. This requires the extremely intense and narrow beam of X-rays provided by the ESRF,” added Dr. Theyencheri Narayanan from the ESRF, another coauthor of the paper.

The results of the research revealed the conformation of the head domains of myosin--the molecular motors that drive filament sliding--in resting muscle, and show that the movements of the myosin motors following muscle activation are much slower than the structural changes in the actin filaments. The different timings of the structural changes reveal the signaling pathway between the actin and myosin filaments in muscle, shedding new light on the mechanism of muscle regulation.

"We were observing quite rapid biological processes, in the order of milliseconds, along with minuscule structural changes, typically 10 nm or less. A human hair is ten-thousand times thicker. To integrate the mechanical and X-ray diffraction methods that are required to resolve the combination of these extremes is a real experimental challenge,” explained Dr. Vincenzo Lombardi, from the University of Florence.

Although the study has no immediate clinical application, its longer-term impact may be in the field of heart disease, in which these essential signaling processes are not working optimally in the heart muscle.

Existing agents to treat heart failure by modulating this signaling pathway are far from ideal. "To develop better drugs for heart failure, it's likely that a better understanding of the molecular mechanisms of muscle regulation is needed, and that may be the long-term contribution of our experiments,” concluded Dr. Irving.

Related Links:
Università di Firenze
King's College London
European Synchrotron Radiation Facility