A trigger for muscular diseases

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A trigger for muscular diseases

Various muscular diseases are associated with changes in the elasticity of the protein titin, but whether these changes are a cause or an effect of disease has been unclear. A study in The Journal of General Physiology helps solve this "chicken or the egg" conundrum and identifies a key player in determining titin's size and stiffness.

Titin is an enormous protein that functions as a molecular spring responsible for the passive elasticity of muscles. It is composed of many individually folded protein domains—including repeating immunoglobulin-like (Ig) domains—that unfold when the protein is stretched and refold when tension is removed.

A team led by researchers from the University of Arizona used a mouse model lacking nine titin Ig domains to investigate the effects of a small increase in titin stiffness. The mutant mice showed a slight curvature of the spine (commonly associated with skeletal muscle disorders), atrophy of the soleus muscle in the leg, atrophy of the diaphragm, and changes in muscle contractility.

In analyzing the mutant mice, the researcher were surprised to observe that in the soleus, which contains one of the largest forms of titin in adult striated muscle, the increase in passive stress was much greater than expected from the loss of only nine Ig domains. And the mutant mice underwent additional changes in titin splicing to produce much smaller, stiffer forms of titin than anticipated. These results indicate that increasing titin's stiffness can be a trigger for—rather than the result of—pathological changes in skeletal muscles.

Further investigation revealed that titin's increased stiffness was caused by an abundance of the splicing factor RBM20 in the mutant mice. Mice created by crossing the mutants with a mouse with decreased RMB20 activity failed to show these additional changes in titin splicing. The results indicate that RMB20 plays a crucial role in determining titin's size and elasticity and could therefore be a possible avenue for modulating the protein in the treatment of various muscular diseases.



INFORMATION:

Buck, D., et al. 2014. J. Gen. Physiol. doi:10.1085/jgp.201311129

About The Journal of General Physiology

Founded in 1918, The Journal of General Physiology (JGP) is published by The Rockefeller University Press. All editorial decisions on manuscripts submitted are made by active scientists in conjunction with our in-house scientific editor. JGP content is posted to PubMed Central, where it is available to the public for free six months after publication. Authors retain copyright of their published works and third parties may reuse the content for non-commercial purposes under a creative commons license. For more information, please visit http://www.jgp.org.

Research reported in the press release was supported by the Bellows Foundation, the ARCS Foundation, the American Heart Association, and the National Institutes of Health.