Open AccessAkt2 ablation prolongs life span and improves myocardial contractile function with adaptive cardiac remodeling: role of Sirt1‐mediated autophagy regulation
Author(s) -
Ren Jun,
Yang Lifang,
Zhu Li,
Xu Xihui,
Ceylan Asli F.,
Guo Wei,
Yang Jian,
Zhang Yingmei
Publication year - 2017
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12616
Subject(s) - mitophagy , autophagy , protein kinase b , parkin , biology , pink1 , foxo1 , foxo3 , pi3k/akt/mtor pathway , mitochondrion , medicine , endocrinology , akt2 , microbiology and biotechnology , phosphorylation , akt1 , signal transduction , apoptosis , biochemistry , disease , parkinson's disease
Summary Aging is accompanied with unfavorable geometric and functional changes in the heart involving dysregulation of Akt and autophagy. This study examined the impact of Akt2 ablation on life span and cardiac aging as well as the mechanisms involved with a focus on autophagy and mitochondrial integrity. Cardiac geometry, contractile, and intracellular Ca 2+ properties were evaluated using echocardiography, IonOptix ® edge‐detection and fura‐2 techniques. Levels of Sirt1, mitochondrial integrity, autophagy, and mitophagy markers were evaluated using Western blot. Our results revealed that Akt2 ablation prolonged life span (by 9.1%) and alleviated aging (24 months)‐induced unfavorable changes in myocardial function and intracellular Ca 2+ handling ( SERCA 2a oxidation) albeit with more pronounced cardiac hypertrophy (58.1%, 47.8%, and 14.5% rises in heart weight, wall thickness, and cardiomyocyte cross‐sectional area). Aging downregulated levels of Sirt1, increased phosphorylation of Akt, and the nuclear transcriptional factor Foxo1, as well as facilitated acetylation of Foxo1, the effects of which (except Sirt1 and Foxo1 acetylation) were significantly attenuated or negated by Akt2 ablation. Advanced aging disturbed autophagy, mitophagy, and mitochondrial integrity as evidenced by increased p62, decreased levels of beclin‐1, Atg7, LC 3B, BNIP 3, PTEN ‐induced putative kinase 1 ( PINK 1), Parkin, UCP ‐2, PGC ‐1α, and aconitase activity, the effects of which were reversed by Akt2 ablation. Aging‐induced cardiomyocyte contractile dysfunction and loss of mitophagy were improved by rapamycin and the Sirt1 activator SRT 1720. Activation of Akt using insulin or Parkin deficiency prevented SRT 1720‐induced beneficial effects against aging. In conclusion, our data indicate that Akt2 ablation protects against cardiac aging through restored Foxo1‐related autophagy and mitochondrial integrity.