Complete loss of murine Xin results in a mild cardiac phenotype with altered distribution of intercalated discs.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, Bonn D-53121, Germany.
Julia
J
Otten
Peter F M
PF
van der Ven
Padmanabhan
P
Vakeel
Stefan
S
Eulitz
Gregor
G
Kirfel
Oliver
O
Brandau
Michael
M
Boesl
Jan W
JW
Schrickel
Markus
M
Linhart
Katrin
K
Hayess
Francisco J
FJ
Naya
Hendrik
H
Milting
Rainer
R
Meyer
Dieter O
DO
Fürst
D000199:Actins / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009202:Cardiomyopathies / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004562:Electrocardiography; D005260:Female; D015870:Gene Expression / Q000502:physiology; D015723:Gene Library; D006801:Humans; D007536:Isomerism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D012518:Sarcomeres / Q000473:pathology; D012720:Severity of Illness Index
D000199:Actins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C512114:XIRP1 protein, human; C118478:Xin protein, mouse