Cardiovascular Research Advance Access first published online on October 19, 2009
This version [Corrected Proof] published online on November 18, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp345
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Complete loss of murine Xin results in a mild cardiac phenotype with altered distribution of intercalated discs
1 Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, Bonn D-53121, Germany
2 Department of Cell Biology, University of Potsdam, Potsdam, Germany
3 Max Planck Institute for Biochemistry, Martinsried, Germany
4 Department of Medicine-Cardiology, University of Bonn, Bonn, Germany
5 Department of Biology, Boston University, Boston, MA 02215, USA
6 Herz- und Diabeteszentrum NRW, Erich und Hanna Klessmann-Institut für Kardiovaskuläre Forschung und Entwicklung, Bad Oeynhausen, Germany
7 Institute of Physiology II, University of Bonn, Wilhelmstr. 31, Bonn, Germany
* Corresponding author. Tel: +49 228 73 5301 (D.O.F.)/+49 228 287 22311 (R.M.), Fax: +49 228 73 5302 (D.O.F.)/+49 228 287 22313 (R.M.), Email: dfuerst{at}uni-bonn.de (D.O.F.)/rainer.meyer{at}ukb.uni-bonn.de (R.M.)
Aims: Xin is a striated muscle-specific F-actin binding protein that has been implicated in cardiomyopathies. In cardiomyocytes, Xin is localized at intercalated discs (IDs). Mice lacking only two of the three Xin isoforms (XinAB–/– mice) develop severe cardiac hypertrophy. To further investigate the function of Xin variants in the mammalian heart, we generated XinABC–/– mice deficient in all Xin isoforms.
Methods and results: XinABC–/– mice showed a very mild phenotype: heart weight, heart weight to tibia length ratios, and cardiac dimensions were not altered. Increased perivascular fibrosis was only observed in hearts of young XinABC–/– mice. Striking differences were revealed in isolated cardiomyocytes: XinABC–/– cells demonstrated a significantly increased number of non-terminally localized ID-like structures. Furthermore, resting sarcomere length was increased, sarcomere shortening, peak shortening at 0.5–1 Hz, and the duration of shortening were decreased, and shortening and relengthening velocities were accelerated at frequencies above 4 Hz in XinABC–/– cardiomyocytes. ECG showed a significantly shorter HV interval and a trend towards shorter QRS interval in XinABC–/– mice, suggesting a faster conduction velocity of the ventricular-specific conduction system. In human cardiac tissue, expression of XinC protein was detected solely in samples from patients with cardiac hypertrophy.
Conclusion: Total Xin deficiency leads to topographical ID alterations, premature fibrosis and subtle changes in contractile behaviour; this is a milder cardiac phenotype than that observed in XinAB–/– mice, which still can express XinC. Together with the finding that XinC is detected solely in cardiomyopathic human tissues, this suggests that its expression is responsible for the stronger dominant phenotype in XinAB–/– mice. Furthermore, it indicates that XinC may be involved in the development of human cardiac hypertrophy.
KEYWORDS Cardiac hypertrophy; Intercalated disc; Xin-repeat protein isoforms; Alternative splicing; Null mutation
Time for primary review: 39 days
Present address. Department of Neuromuscular and Cardiovascular Cell Biology, Max-Delbrück-Center, Berlin, Germany.
Present address. Institute for Physiology, Ludwig-Maximilians-University of Munich, Germany.
¶ Present address. Max Planck Institute of Neurobiology, Transgenic Service, Martinsried, Germany.
Present address. Bundesinstitut für Risikobewertung - ZEBET, Berlin, Germany.