Sci. Aging Knowl. Environ., 6 April 2005
Under tension, massive muscle protein relays signal to nucleus
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2005/14/nf27
It's a stretch to connect muscle fibers and genes, a new study suggests. Working muscles activate genes when they elongate a giant protein within their cells, the work reveals. Faults in the system underlie a rare muscle disease, but glitches might also contribute to weakness in the elderly.
Muscle fibers contract when bundles of myosin and actin proteins--gathered in segments called sarcomeres--pull against each other. Titin, the longest and heaviest protein known, links myosin and actin filaments and stretches during muscle activity, keeping sarcomeres springy. Titin might also transmit messages that govern the activity of muscle genes. It contains a so-called tyrosine kinase (TK) region that glues phosphate groups onto other proteins, a common cellular signal. In a new study, molecular cardiologist Mathias Gautel of Kings College London in the United Kingdom and colleagues wondered whether the protein senses muscle stretching and alters gene activity.
Titin's TK segment is hidden when the protein is relaxed and exposed when it extends. The researchers generated portions of titin that mimic the two forms and searched among muscle proteins for molecules that cling only to the open version. One such protein, called Nbr1, adhered to p62, which in turn grabbed a protein called MuRF2. Further experiments support the idea that these proteins muster on titin. Nbr1, p62, and MuRF2 clump in muscle cells and gather near the TK region.
Next, the scientists investigated how titin stretching in muscle cells influences the protein gang. The researchers cultured rat heart muscle cells and halted their contractions using chemicals. In response, p62 wandered from sarcomeres, and MuRF2 journeyed to cell nuclei. The team showed that MuRF2 grabs a protein called SRF, which activates genes in muscle cells that replenish muscle fibers. Moreover, as MuRF2 accumulated in the nucleus, quantities of SRF there dropped, and the activity of SRF-controlled genes plummeted. The findings suggest that when muscle activity ceases, titin jettisons MuRF2, which shuts down muscle-maintenance genes.
Further experiments support the idea. Individuals with a rare disease have flaccid muscles with disorganized fibers, and they die as early as age 40 because their respiratory muscles fail. The researchers found that these individuals carry mutations in titin's TK portion. Together, the findings suggest that titin serves as a "mechanical feedback mechanism" between muscle fibers and genes, says Gautel. The pathway might encourage muscle atrophy in sedentary or infirm people, especially the elderly, he says.
The paper "opens a new door for understanding muscle regeneration and muscle remodeling," says cellular and molecular biologist Vittorio Sartorelli of the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Maryland. For instance, abnormal contractions after a heart attack might prod titin and induce gene-activity changes that promote scar tissue or overgrowth of heart cells, he speculates. Drugs that prevent MuRF2 from entering the nucleus might prevent muscle deterioration, he adds. The study is "a great accomplishment," says titin researcher Henk Granzier of Washington State University in Pullman. However, he notes that further work is necessary to "really nail down that ... biomechanics" are responsible for changes in gene activity. Extending the findings might reveal ways to keep older muscle flexing.
April 6, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150