Ultrastructural remodelling of Ca(2+) signalling apparatus in failing heart cells.
OBJECTIVE
The contraction of a heart cell is controlled by Ca(2+)-induced Ca(2+) release between L-type Ca(2+) channels (LCCs) in the cell membrane/T-tubules (TTs) and ryanodine receptors (RyRs) in the junctional sarcoplasmic reticulum (SR). During heart failure, LCC-RyR signalling becomes defective. The purpose of the present study was to reveal the ultrastructural mechanism underlying the defective LCC-RyR signalling and contractility.


RESULTS
In rat models of heart failure produced by transverse aortic constriction surgery, stereological analysis of transmission electron microscopic images showed that the volume density and the surface area of junctional SRs and those of SR-coupled TTs were both decreased in failing heart cells. The TT-SR junctions were displaced or missing from the Z-line areas. Moreover, the spatial span of individual TT-SR junctions was markedly reduced in failing heart cells. Numerical simulation and junctophilin-2 knockdown experiments demonstrated that the decrease in junction size (and thereby the constitutive LCC and RyR numbers) led to a scattered delay of Ca(2+) release activation.


CONCLUSIONS
The shrinking and eventual absence of TT-SR junctions are important mechanisms underlying the desynchronized and inhomogeneous Ca(2+) release and the decreased contractile strength in heart failure. Maintaining the nanoscopic integrity of TT-SR junctions thus represents a therapeutic strategy against heart failure and related cardiomyopathies.
State Key Laboratory of Biomembrane and Membrane Biotechnology, Key Laboratory of Cell Proliferation and Differentiation, Key Laboratory of Molecular Cardiovascular Sciences, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides,  Third Hospital, and College of Life Sciences, Peking University, Beijing 100871,  China.
Hao-Di
HD
Wu
Ming
M
Xu
Rong-Chang
RC
Li
Liang
L
Guo
Ying-Si
YS
Lai
Shi-Ming
SM
Xu
Su-Fang
SF
Li
Quan-Long
QL
Lü
Lin-Lin
LL
Li
Hai-Bo
HB
Zhang
You-Yi
YY
Zhang
Chuan-Mao
CM
Zhang
Shi-Qiang
SQ
Wang
D000200:Action Potentials; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure*; D048430:Cell Shape; D002478:Cells, Cultured; D003198:Computer Simulation; D004195:Disease Models, Animal; D056966:Excitation Contraction Coupling; D055785:Gene Knockdown Techniques; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008955:Models, Cardiovascular; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure*; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure*; D013997:Time Factors; D014162:Transfection
D020746:Calcium Channels, L-Type; D008565:Membrane Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C412507:junctophilin