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March 5, 2026Journal of Translational MedicineOpen Access

Defective energy substrate oxidation and BCAA accumulation characterize advanced heart failure in mice and humans.

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Why the study?

Molecular mechanisms and causal relationships linking defective catabolism of alternative, glucose-sparing fuels to altered glucose metabolism in heart failure remain unknown.

Population

Tgαq*44 mice aged 4-14 months plus 20 HF cases and 18 non-failing controls

Comparison

Tgαq*44 mice vs controls across ages, and HF cases vs non-failing controls

Design

Preclinical animal model study with a human validation cohort

Key result

Defects in fatty acid, pyruvate, branched-chain amino acid, and ketone body oxidation alongside elevated lactate characterized overt heart failure in Tgαq*44 mice and were mirrored by BCAA accumulation and disrupted glucose oxidation in patients with advanced heart failure.

Authors

MOMariola OlkowiczAJAgata JędrzejewskaUTUrszula Tyrankiewicz

Discussion

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Overview

Highlights potential metabolic therapies in advanced HF but should not yet change practice; extends animal models to humans and leaves therapeutic targeting open.

Key Points

  • To investigate the relationship between cardiac energy substrate preference and heart failure progression in Tgαq*44 mice.
  • Analyzed cardiac protein expression in Tgαq*44 mice aged 4−14 months
  • Examined energy substrate preference and high-energy phosphate metabolism
  • Assessed plasma metabolites in a cohort of heart failure cases and controls
  • Increased reliance on glucose and reduced mitochondrial oxidative metabolism observed
  • Impaired pyruvate utilisation via mitochondrial pyruvate carrier was noted
  • Defective oxidation of fatty acids, branched-chain amino acids, and ketone bodies identified in end-stage heart failure
  • Elevated lactate levels and chronic accumulation of branched-chain amino acids found in advanced heart failure patients

Structured PICO

P
Population
Female Tgαq*44 mice (heart failure model) and age-matched female wild-type FVB control mice at 4, 8, 10, 12, and 14 months of age. A translational human cohort included n=20 heart failure cases with ejection fraction <50% and n=18 non-failing controls.
I
Intervention
Tgαq*44 transgenic model of slowly developing chronic heart failure (overexpression of HA-tagged, constitutively activated Gαq protein)
C
Comparator
Age-matched wild-type FVB mice and non-failing human controls
O
Outcome
Alterations in cardiac protein expression, energy substrate preference, high-energy phosphate metabolism, and plasma metabolitessurrogate

The transition to overt heart failure is marked by defective auxiliary fuel (BCAA, ketone) oxidation and impaired mitochondrial pyruvate transport, highlighting potential metabolic therapeutic targets.

Limitations

  • Small cohort of human patients (n=38) limits generalizability.
  • Study uses a mouse model (Tgαq*44) that may not fully replicate human HF pathophysiology.
  • Primary endpoint results lack exact quantitative effect sizes or p-values in presented abstract.

Cite This Study

Olkowicz et al. (2026) studied Patients with heart failure with reduced ejection fraction (EF <50%) at time of diagnosis (n=38). Defects in fatty acid, pyruvate, branched-chain amino acid, and ketone body oxidation alongside elevated lactate characterized overt heart failure in Tgαq*44 mice and were mirrored by BCAA accumulation and disrupted glucose oxidation in patients with advanced heart failure.

synapsesocial.com/papers/69a91df9d6127c7a504c15e7https://doi.org/10.1186/s12967-026-07883-y
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