TY - JOUR
T1 - Junctophilin-2 is necessary for T-tubule maturation during mouse heart development
AU - Reynolds, Julia O.
AU - Chiang, David Y.
AU - Wang, Wei
AU - Beavers, David L.
AU - Dixit, Sayali S.
AU - Skapura, Darlene G.
AU - Landstrom, Andrew P.
AU - Song, Long Sheng
AU - Ackerman, Michael J.
AU - Wehrens, Xander H.T.
N1 - Funding Information:
This work was supported by a W.M. Keck Foundation Distinguished Young Scholar in Medical Research Award, an Established Investigator of the American Heart Association (AHA), and grants from the Muscular Dystrophy Association and NIH (HL089598 and HL091947) (to X.H.T.W.). D.Y.C. and D.L.B. are supported by AHA predoctoral fellowships, and D.L.B. was supported by NIH grant T32HL007676-21A1. M.J.A. is also an Established Investigator of the AHA and is supported by NIH grants HD42569 and HL94291, and the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. L.-S.S. is supported by NIH grant HL090905 and AHA scientist development grant 0635056N. This work was also supported in part by Fondation Leducq (‘Alliance for CaMKII Signaling in Heart’) to X.H.T.W. and M.J.A.
PY - 2013/10/1
Y1 - 2013/10/1
N2 - Aims: Transverse tubules (TTs) provide the basic subcellular structuresthat facilitate excitation-contraction (EC) coupling, the essential process that underlies normal cardiac contractility. Previous studies have shown that TTs develop within thefirst few weeks of life in mammals but the molecular determinants of this development have remained elusive. This study aims to elucidate the role of junctophilin-2 (JPH2), a junctional membrane complex protein, in the maturation of TTs in car-diomyocytes. Methods and results: Using a novel cardiac-specific short-hairpin-RNA-mediated JPH2 knockdown mouse model (Mus musculus; αMHC-shJPH2), weassessed the effects of the loss of JPH2 on the maturation of the ventricular TT structure. Between embryonic day (E) 10.5 and postnatal day (P) 10, JPH2 mRNA and protein levels were reduced by >70% in αMHC-shJPH2 mice. At P8 and P10, knockdown of JPH2 significantly inhibited the maturation of TTs, while expression levels of other genes implicated in TT development remained mostly unchanged. At the same time, intracellular Ca2+ handling was disrupted in ventricular myocytes from αMHC-shJPH2 mice, which developed heart failure by P10 marked by reduced ejection fraction, ventricular dilation, and premature death. In contrast, JPH2 transgenic mice exhibited accelerated TT maturation by P8. Conclusion: Our findings suggest that JPH2 is necessary for TT maturation during postnatal cardiac developmentin mice. In particular, JPH2 may be critical in anchoring the invaginating sarcolemma to the sarcoplasmic reticulum, thereby enabling the maturation of the TT network.
AB - Aims: Transverse tubules (TTs) provide the basic subcellular structuresthat facilitate excitation-contraction (EC) coupling, the essential process that underlies normal cardiac contractility. Previous studies have shown that TTs develop within thefirst few weeks of life in mammals but the molecular determinants of this development have remained elusive. This study aims to elucidate the role of junctophilin-2 (JPH2), a junctional membrane complex protein, in the maturation of TTs in car-diomyocytes. Methods and results: Using a novel cardiac-specific short-hairpin-RNA-mediated JPH2 knockdown mouse model (Mus musculus; αMHC-shJPH2), weassessed the effects of the loss of JPH2 on the maturation of the ventricular TT structure. Between embryonic day (E) 10.5 and postnatal day (P) 10, JPH2 mRNA and protein levels were reduced by >70% in αMHC-shJPH2 mice. At P8 and P10, knockdown of JPH2 significantly inhibited the maturation of TTs, while expression levels of other genes implicated in TT development remained mostly unchanged. At the same time, intracellular Ca2+ handling was disrupted in ventricular myocytes from αMHC-shJPH2 mice, which developed heart failure by P10 marked by reduced ejection fraction, ventricular dilation, and premature death. In contrast, JPH2 transgenic mice exhibited accelerated TT maturation by P8. Conclusion: Our findings suggest that JPH2 is necessary for TT maturation during postnatal cardiac developmentin mice. In particular, JPH2 may be critical in anchoring the invaginating sarcolemma to the sarcoplasmic reticulum, thereby enabling the maturation of the TT network.
KW - Developmental biology
KW - E-C coupling
KW - Junctophilin-2
KW - Transverse tubules
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U2 - 10.1093/cvr/cvt133
DO - 10.1093/cvr/cvt133
M3 - Article
C2 - 23715556
AN - SCOPUS:84887944835
SN - 0008-6363
VL - 100
SP - 44
EP - 53
JO - Cardiovascular research
JF - Cardiovascular research
IS - 1
ER -