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April 15, 2026MetabolismOpen Access

Cardiomyocyte AKT1 and AKT2 deletion in mice induces lethal heart failure and ~25% lower phosphocreatine/ATP ratios.

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Why the study?

The mammalian heart depends on oxidative metabolism to meet ATP demands, and AKT regulates growth and metabolism, but the effect of simultaneous deletion of AKT1 and AKT2 in the adult heart was unknown.

Population

Adult mice

Comparison

Inducible cardiomyocyte-specific AKT1 and AKT2 double knockout vs baseline or controls

Design

Preclinical animal study

Key result

Simultaneous deletion of cardiomyocyte AKT1 and AKT2 in mice induced lethal heart failure and energetic depletion, evidenced by a drop in cardiac phosphocreatine/ATP ratios from 2 to 1.5.

Authors

SGStefanie GödeckeAHAndré HeinenTATim Appel

Discussion

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Overview

Warrants caution with pan-AKT inhibitors in oncology; confirms redundant essential roles of AKT1/2 in cardiac energetics and HF prevention.

Key Points

  • This research aims to understand how the loss of AKT signaling affects lipid metabolism and heart function in cardiac myocytes.
  • Utilized inducible cardiomyocyte-specific AKT1 AKT2 double knockout mice.
  • Performed metabolic analyses using respirometry and Seahorse flux analysis on cardiac tissue.
  • Conducted in vivo NMR spectroscopy and CrCEST imaging to assess cardiac energetics.
  • Executed transcriptomic and proteomic studies to analyze gene expression related to metabolism.
  • Double knockout mice exhibited rapid heart failure and cardiomyocyte atrophy.
  • Fatty acid metabolism significantly declined, while glucose metabolism was relatively maintained.
  • Cardiac phosphocreatine/ATP ratios decreased from 2 to 1.5, indicating energy depletion.
  • Key metabolic genes involved in the TCA cycle and oxidative phosphorylation were down-regulated.
  • Loss of perilipins and associated proteins led to decreased ability to store fatty acids in lipid droplets.

Structured PICO

P
Population
Adult mice with inducible cardiomyocyte-specific AKT1 AKT2 double knockout
I
Intervention
Simultaneous deletion of cardiac isoforms AKT1 and AKT2
O
Outcome
Cardiac function, metabolism (fatty acid and glucose), and cellular atrophysurrogate

Isoform-independent AKT signaling in cardiac myocytes is indispensable for preserving cardiac fatty acid metabolism and energy supply, preventing lethal heart failure and cellular atrophy.

Cite This Study

Gödecke et al. (2026) studied this question. Simultaneous deletion of cardiomyocyte AKT1 and AKT2 in mice induced lethal heart failure and energetic depletion, evidenced by a drop in cardiac phosphocreatine/ATP ratios from 2 to 1.5.

synapsesocial.com/papers/69df2a4be4eeef8a2a6af743https://doi.org/10.1016/j.metabol.2026.156619
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1AMPK deficiency in cardiac muscle results in dilated cardiomyopathy in the absence of changes in energy metabolism2015 · 74 citations
  2. 2AMP-Activated Protein Kinase α2 Deficiency Affects Cardiac Cardiolipin Homeostasis and Mitochondrial Function2007 · 53 citations
  3. 3Compromised Energetics in the Adenylate Kinase AK1Gene Knockout Heart under Metabolic Stress2000 · 81 citations
  4. 4Interference with Akt Signaling Protects Against Myocardial Infarction and Death by Limiting the Consequences of Oxidative Stress2013 · 42 citations
  5. 5Spatiotemporal AMPKα2 deletion in mice induces cardiac dysfunction, fibrosis and cardiolipin remodeling associated with mitochondrial dysfunction in males only2021 · 21 citations