April 21, 2008

Understanding How Heart Muscle Forms

Microscopic field showing several sarcomeres, each with a heavy black line at either end. Sets of lighter parallel filaments extend about a quarter of the way toward the centers. The filaments filling the middle half are darker Transmission electron micrograph showing sarcomeres, which extend from one heavy black line to the next. The actin filaments extend from the ends towards the centers of the sarcomeres. Myosin forms the darker bands at the center of the sarcomeres. A molecular motor protein, myosin pulls on the actin filaments, causing them to slide inward and the muscle to contract.University of Edinburgh and Wellcome Images.

Synchronized pulsing of heart muscle cells allows the heart to pump blood through the body. A new study has identified a protein that helps organize the structures that produce the contractions in these cells.

Researchers have long known that muscle cells have subunits called sarcomeres that create the contractions that make muscles move. Sarcomeres are made of 2 parallel, overlapping sets of filaments composed mainly of the proteins myosin and actin. Myosin is a molecular motor that pulls on the long actin filaments to produce muscle contraction. What researchers haven't yet figured out is how muscle cells organize these networks of actin filaments in the first place.

A protein called leiomodin first sparked researchers' interests when they noticed that its sequence seemed to have the sites necessary to bind actin. Dr. Roberto Dominguez at the University of Pennsylvania School of Medicine led a research team working to further explore the role of leiomodin with funding from NIH's National Heart, Lung and Blood Institute (NHLBI) and National Institute of General Medical Sciences (NIGMS). In Science on April 11, 2008, they revealed that leiomodin is present in the sarcomeres of muscle cells and is responsible for the initial assembly of actin filaments.

By attaching a fluorescent protein to leiomodin, the researchers were able to visualize the protein under the microscope in heart muscle cells. They found that leiomodin was bound to the actin filaments in sarcomeres.

When they then produced higher-than-normal levels of leiomodin in heart muscle cells, the scientists noticed disordered sarcomeres. They also saw actin filaments in regions of the cell where filaments don't usually form. Cells made to produce less leiomodin, in contrast, had disrupted sarcomeres with short, unaligned actin bunches. Together, these experiments show that leiomodin is essential for organization of the sarcomere.

When the researchers added leiomodin to pools of fluorescently labeled actin subunits, they were able to watch new actin filaments form under the microscope. The higher the concentration of leiomodin they added, the more actin filaments were produced. Leimodin, they concluded, is able to act as a "nucleator," causing new actin filaments to begin forming.

"For a long time, physiologists have wondered what serves as the nucleator protein in cardiac muscle cells," says co-author Dr. Thomas Pollard of Yale University. "It was very satisfying after all these years to discover that leiomodin can serve as the nucleator protein to initiate the formation of actin polymers in heart muscle cells."

Future studies will be needed to reveal whether mutations in leiomodin are found in the population and whether they contribute to heart defects. Further experiments will also need to determine if leiomodin has an equally essential role in skeletal muscle cells.

—by Vanessa C. McMains

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