In a study published today in Nature Communications, researchers developed a mouse model that enabled them to identify the proteins involved in sarcomere contraction, relaxation, communication, and adaptation. Specifically, they were able to map proteins in defined subregions of the sarcomere, starting from the Z-disc.
In the mouse model, an artificial enzyme called BioID was inserted into the large protein titin. The Titin-BioID complex then tagged proteins that were close to the Z-disc. “Titin-BioID probes specific regions of the sarcomere structure in vivo,” says coauthor Philipp Mertins of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). “This has not been possible before.”
The team was the first to use BioID in live animals under physiological conditions, and they identified 450 proteins associated with the sarcomere. Of these, about half were already known. They found striking differences between heart and skeletal muscle and between adult and neonatal mice.
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“We wanted to know who’s there, know who the players are,” Gotthardt says. “Most were expected, validating our approach.”
The protein that they were not expecting to see in the Z-disc was myosin, which is integrated at the opposite site of the sarcomere. When a muscle is triggered to move, myosin walks along actin bringing neighboring Z-discs closer together. This sliding of actin and myosin filaments creates the force. However, current models have had trouble predicting the behavior of fully contracted sarcomeres—but these models have assumed myosin does not enter the Z-disc on its walk along actin.
The researchers plan to next use BioID to study animals with different pathologies, to see what proteins are involved in muscle atrophy, for example. “Maybe a protein that is not normally there goes into the sarcomere, and it is part of the pathology,” Gotthardt says. “We can find it with BioID.”
Image: Watching the sarcomeres contract - collage of myosin (green), actin and the Z-disk (red), and BioID (blue).