title: Functional role of Calstabin2 in age-related cardiac alterations.
abstract: Calstabin2 is a component of the cardiac ryanodine receptor (RyR2) macromolecular complex, which modulates Ca(2+) release from the sarcoplasmic reticulum in cardiomyocytes. Previous reports implied that genetic deletion of Calstabin2 leads to phenotypes related to cardiac aging. However, the mechanistic role of Calstabin2 in the process of cardiac aging remains unclear. To assess whether Calstabin2 is involved in age-related heart dysfunction, we studied Calstabin2 knockout (KO) and control wild-type (WT) mice. We found a significant association between deletion of Calstabin2 and cardiac aging. Indeed, aged Calstabin2 KO mice exhibited a markedly impaired cardiac function compared with WT littermates. Calstabin2 deletion resulted also in increased levels of cell cycle inhibitors p16 and p19, augmented cardiac fibrosis, cell death, and shorter telomeres. Eventually, we demonstrated that Calstabin2 deletion resulted in AKT phosphorylation, augmented mTOR activity, and impaired autophagy in the heart. Taken together, our results identify Calstabin2 as a key modulator of cardiac aging and indicate that the activation of the AKT/mTOR pathway plays a mechanistic role in such a process.
authors.affiliation: 1] National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China [2] Department of Physiology and Cellular Biophysics, Wu Center for Molecular Cardiology, Columbia University Medical Center, College of Physicians &Surgeons, New York, NY (USA).
authors.forename: Qi
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: School of Life Sciences, Northeast Normal University, Changchun 130024, PR China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Physiology and Cellular Biophysics, Wu Center for Molecular Cardiology, Columbia University Medical Center, College of Physicians &Surgeons, New York, NY (USA).
authors.forename: Gaetano
authors.initials: G
authors.lastname: Santulli
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Gu
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Zhi-Guang
authors.initials: ZG
authors.lastname: Yang
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Zeng-Qiang
authors.initials: ZQ
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, College of Life Sciences, Peking University, Beijing, China.
authors.forename: Yan-Ting
authors.initials: YT
authors.lastname: Zhao
authors.affiliation: Institute of Translational Medicine, Nanchang University, Honggu District, Nanchang, China.
authors.forename: Hong-Bo
authors.initials: HB
authors.lastname: Xin
authors.affiliation: Institute of Translational Medicine, Nanchang University, Honggu District, Nanchang, China.
authors.forename: Ke-Yu
authors.initials: KY
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, College of Life Sciences, Peking University, Beijing, China.
authors.forename: Shi-Qiang
authors.initials: SQ
authors.lastname: Wang
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Guangju
authors.initials: G
authors.lastname: Ji
mesh_terms: D000375:Aging; D000818:Animals; D001343:Autophagy; D019703:Calcineurin / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence; D017379:Hypertrophy, Left Ventricular / Q000473:pathology; D008297:Male; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000502:physiology; D015398:Signal Transduction; D022021:Tacrolimus Binding Proteins / Q000502:physiology*; D020257:Ventricular Remodeling
chemical_list: D019703:Calcineurin; D022021:Tacrolimus Binding Proteins; C509259:FKBP1B protein, mouse