Genetic Deletion of Fkbp12.6 Accelerates Cardiac Aging in Mice

Abstract

Aims: Cardiac aging is one of the main causes of heart dysfunction and other cardiac diseases. FK506 binding protein 12.6 (FKBP12.6) modulates Ca2+ release from the sarcoplasmic reticulum in cardiomyocytes. Previous studies implied that genetic deletion of FKBP12.6 leads to cardiac aging related phenotypes. However, the role and mechanism of FKBP12.6 in the process of cardiac aging remain unclear.Methods and Results: To assess whether FKBP12.6 is involved in cardiac aging and age-related heart dysfunction, FKBP12.6 knockout (KO) and control littermate mice were used throughout the study. We found a significant association between deletion of FKBP12.6 and cardiac aging. Indeed, aged FKBP12.6 KO mice exhibited markedly impaired cardiac function compared to wild-type. Strikingly, FKBP12.6 deletion resulted also in increased levels of cell cycle inhibitors p16 and p19, augmented cardiac fibrosis, cell death, and shorter telomeres. Finally, we demonstrated that FKBP12.6 deletion enhanced insulin signaling in the hearts, resulting in AKT phosphorylation, augmented mTOR activity, and impaired autophagy.Conclusions: Taken together, these results identify that genetic deletion of FKBP12.6 promotes cardiac aging and indicate that the activation of the AKT/mTOR pathway plays a mechanistic role in the process.