Abstract
Z-disks, the mechanical integration sites of heart and skeletal muscle cells, link anchorage of myofilaments to force reception and processing. The key molecules that enable the Z-disk to persistently withstand the extreme mechanical forces during muscle contraction have not yet been identified. Here we isolated nexilin (encoded by NEXN) as a novel Z-disk protein. Loss of nexilin in zebrafish led to perturbed Z-disk stability and heart failure. To evaluate the role of nexilin in human heart failure, we performed a genetic association study on individuals with dilated cardiomyopathy and found several mutations in NEXN associated with the disease. Nexilin mutation carriers showed the same cardiac Z-disk pathology as observed in nexilin-deficient zebrafish. Expression in zebrafish of nexilin proteins encoded by NEXN mutant alleles induced Z-disk damage and heart failure, demonstrating a dominant-negative effect and confirming the disease-causing nature of these mutations. Increasing mechanical strain aggravated Z-disk damage in nexilin-deficient skeletal muscle, implying a unique role of nexilin in protecting Z-disks from mechanical trauma.
| Original language | English |
|---|---|
| Journal | Nature Medicine |
| Volume | 15 |
| Issue number | 11 |
| Pages (from-to) | 1281-1288 |
| Number of pages | 8 |
| ISSN | 1078-8956 |
| DOIs | |
| Publication status | Published - 01.11.2009 |
Funding
We thank S. Marquart, S. Weber, S. Kolb, H. Hosser, O. Mücke and S. Manthey as well as S. Wrobel for their excellent technical support. We thank B. Jurmann for human subject work-up and evaluation of clinical data and N. Frey (University of Heidelberg) for providing the calsarcin-specific antibody. We thank R. Knöll and L. Thierfelder for critical discussion of patient data. This work was supported by Deutsche Forschungsgemeinschaft Ro2173/1-1, Ro2173/2-1, Ro2173/2-2 and Ro2173/3-1 (W.R.), Bundesministerium für Bildung und Forschung 01GS0108, 01GS0420 and 01GS0836 (W.R., B.M., D.W. and H.A.K.) and the Postdoc-Fellowship YIA of the medical faculty of the University of Heidelberg (T.D.). We are indebted to all probands for their participation. We thank M.C. Fishman for critical discussion of the manuscript.
