Akt2 Regulates Cardiac Metabolism and Cardiomyocyte Survival

Brian Debosch,Nandakumar Sambandam,Carla Weinheimer,Michael Courtois,Anthony J Muslin

doi:10.1074/jbc.m513087200

Brian Debosch, Nandakumar Sambandam + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m513087200

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Abstract

The Akt family of serine-threonine kinases participates in diverse cellular processes, including the promotion of cell survival, glucose metabolism, and cellular protein synthesis. All three known Akt family members, Akt1, Akt2 and Akt3, are expressed in the myocardium, although Akt1 and Akt2 are most abundant. Previous studies demonstrated that Akt1 and Akt3 overexpression results in enhanced myocardial size and function. Yet, little is known about the role of Akt2 in modulating cardiac metabolism, survival, and growth. Here, we utilize murine models with targeted disruption of the akt2 or the akt1 genes to demonstrate that Akt2, but not Akt1, is required for insulin-stimulated 2-[(3)H]deoxyglucose uptake and metabolism. In contrast, akt2(-/-) mice displayed normal cardiac growth responses to provocative stimulation, including ligand stimulation of cultured cardiomyocytes, pressure overload by transverse aortic constriction, and myocardial infarction. However, akt2(-/-) mice were found to be sensitized to cardiomyocyte apoptosis in response to ischemic injury, and apoptosis was significantly increased in the peri-infarct zone of akt2(-/-) hearts 7 days after occlusion of the left coronary artery. These results implicate Akt2 in the regulation of cardiomyocyte metabolism and survival.

Highlights

A comparable phenotype was observed in response to cardiac overexpression of activated Akt3, whereas no observable cardiac growth defects were detectable in Akt3-deficient mice at baseline [6]
Insulin-stimulated Glucose Uptake Depends on phosphatidylinositol 3-kinase (PI3K) in insulin (5 min) in the presence of 1 ␮Ci/ml 2DG. 2DG uptake Cultured Cardiomyocytes—Cardiomyocytes express two in response to insulin was not impaired in akt1Ϫ/Ϫ AMCMs transmembrane glucose transporters, GLUT1 and GLUT4, when compared with WT AMCMs (Fig. 2B)
Basal and insulin-dependent glucose transport depends on the 2DG uptake was modestly elevated in akt1Ϫ/Ϫ AMCMs, and translocation of GLUT4 from intracellular vesicles to the this may be due to increased GLUT1 protein levels observed in plasma membrane [21]

Summary

EXPERIMENTAL PROCEDURES

Maintenance of akt1Ϫ/Ϫ and akt2Ϫ/Ϫ Mice—Mice with targeted disruption of the akt or the akt genes were generated as previously described [14, 15]. B, preserved insulin-stimulated glucose uptake in akt1Ϫ/Ϫ AMCMs. Serum-deprived AMCMs from 8-week-old WT and akt1Ϫ/Ϫ mice were treated with vehicle or with 2 nM insulin in the presence of [3H]2DG for 5 min. B, reduced insulinstimulated glucose uptake in akt2Ϫ/Ϫ AMCMs. Serum-deprived AMCMs from 8-week-old WT and akt2Ϫ/Ϫ mice were treated with vehicle or with 2 nM insulin in the presence of [3H]2DG for 5 min. The following two-tailed, two sample t tests were performed with Bonferroni post-hoc correction (two hypotheses): WT-stimulated versus WT control, and WT-stimulated versus akt2Ϫ/Ϫ-stimulated. The following two-tailed, two sample t tests were performed with Bonferroni post-hoc correction (two hypotheses): WT-stimulated versus WT control, WT-stimulated versus akt2ϩ/Ϫ-stimulated. Address this issue, AMCMs derived from akt1Ϫ/Ϫ and akt2Ϫ/Ϫ mice were analyzed for insulin-stimulated signal transduction and glucose uptake.

RESULTS

To examine whether reduced

DISCUSSION