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Functional role of Calstabin2 in age-related cardiac alterations
Qi Yuan1, Zheng Chen2, Gaetano Santulli3
11] 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).
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.
Insights
Calstabin2 deficiency accelerates cardiac aging by impairing heart function and promoting cellular damage. This study reveals Calstabin2 as a key regulator in the aging heart, linked to the AKT/mTOR pathway.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Aging Research
Background:
- Calstabin2 is part of the cardiac ryanodine receptor (RyR2) complex, regulating calcium release in heart cells.
- Previous studies suggested a link between Calstabin2 genetic deletion and cardiac aging phenotypes, but mechanisms were unclear.
Purpose of the Study:
- To investigate the mechanistic role of Calstabin2 in age-related heart dysfunction.
- To determine if Calstabin2 influences cardiac aging processes.
Main Methods:
- Comparison of cardiac function and aging markers between Calstabin2 knockout (KO) mice and wild-type (WT) littermates.
- Analysis of cell cycle inhibitors, fibrosis, cell death, telomere length, and key signaling pathways (AKT/mTOR, autophagy).
Main Results:
- Calstabin2 KO mice showed significantly impaired cardiac function compared to WT mice, especially at older ages.
- Calstabin2 deletion led to increased p16 and p19 levels, fibrosis, cell death, and shorter telomeres.
- Calstabin2 deficiency resulted in AKT phosphorylation, enhanced mTOR activity, and impaired autophagy in the heart.
Conclusions:
- Calstabin2 is identified as a critical modulator of cardiac aging.
- Activation of the AKT/mTOR pathway is mechanistically involved in Calstabin2-mediated cardiac aging.
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