Functional role of Calstabin2 in age-related cardiac alterations

Qi Yuan, Zheng Chen, Gaetano Santulli, Lei Gu, Zhi Guang Yang, Zeng Qiang Yuan, Yan Ting Zhao, Hong Bo Xin, Ke Yu Deng, Shi Qiang Wang, Guangju Ji

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Abstract

Calstabin2 is a component of the cardiac ryanodine receptor (RyR2) macromolecular complex, which modulates Ca2+ 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.

Original languageEnglish (US)
Article number7425
JournalScientific reports
Volume4
DOIs
StatePublished - Dec 11 2014

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Yuan, Q., Chen, Z., Santulli, G., Gu, L., Yang, Z. G., Yuan, Z. Q., Zhao, Y. T., Xin, H. B., Deng, K. Y., Wang, S. Q., & Ji, G. (2014). Functional role of Calstabin2 in age-related cardiac alterations. Scientific reports, 4, [7425]. https://doi.org/10.1038/srep07425