Akt2 ablation prolongs life span and improves myocardial contractile function with adaptive cardiac remodeling: role of Sirt1‐mediated autophagy regulation

Abstract

SummaryAging 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 Ca2+ 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 Ca2+ handling (SERCA2a 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, LC3B, BNIP3, PTEN‐induced putative kinase 1 (PINK1), 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 SRT1720. Activation of Akt using insulin or Parkin deficiency prevented SRT1720‐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.

Metformin mediates cardioprotection against aging‐induced ischemic necroptosis

“…Consistent with these functions, autophagy constitutes a stress adaptation to avoid cardiomyocyte death, although massive autophagy activation may be detrimental for the heart under certain stress conditions. It is important that during the aging process, cardiac autophagy is progressively suppressed (Ren, Sowers, & Zhang, ; Shirakabe et al, ); thus, downregulating autophagy may underlie the progression of cardiac aging (Linton, Gurney, Sengstock, Mentzer, & Gottlieb, ; Ren et al, ). Age‐related pathologies and the aging process itself are accompanied by impaired protein quality control, dysfunctional protein accumulation, and proteostasis imbalance, all of which contribute to increased susceptibility to stress (Sciarretta et al, ).…”

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

“…Other groups also reported the function of AKT in aging. AKT2 ablation prolonged lifespan and improved cardiac aging through restored FOXO 1‐related autophagy and mitochondrial integrity (Ren et al, 2017), and chronic AKT activation accentuated aging‐induced cardiac hypertrophy and myocardial contractile dysfunction through a loss of autophagic regulation (Hua et al, 2011). …”

Metformin inhibits high glucose‐induced mesangial cell proliferation, inflammation and ECM expression through the SIRT1‐FOXO1‐autophagy axis

“…SIRT1 has a wide range of targets, including the transcription factor forkhead box class O (FOXO) 1, which is tightly associated with autophagy induction . SIRT1 can regulate autophagy by deacetylating and activating FOXO . Our previous work indicated that metformin inhibits the in vitro expression of inflammatory cytokines and activation of nuclear factor‐κB induced by high glucose in rat glomerular mesangial cells.…”