In vivo assessment of the recovery of myocardial pyruvate dehydrogenase activity following a ketogenic diet
Year: 2026
Type: article
Abstract: AIMS: A ketogenic diet (KD) can suppress cardiac carbohydrate utilization, which may adversely impact heart function. However, the reversibility of KD-induced metabolic changes is poorly understood. This study aims to characterize myocardial pyruvate dehydrogenase (PDH) flux during the transition from a prolonged KD to a normal chow diet (ND). METHODS AND RESULTS: Cardiac metabolism was longitudinally assessed in rats using hyperpolarized [1-13C]pyruvate at baseline, during a KD (2 and 5 weeks), and a subsequent ND (1, 2, 5, and 8 days) after the 5-week KD. Hyperpolarized 13C products were compared between the KD group and age-matched ND controls. In parallel, nuclear magnetic resonance isotopomer analysis of cardiac tissue with an injection of [3-13C]pyruvate and [1,2-13C2]acetate was performed along with ex vivo enzymatic analysis of PDH activity. Myocardial [13C]bicarbonate production relative to total 13C products decreased from 8.56 ± 2.29% at baseline to 0.46 ± 0.27% after 5 weeks of KD. Reverting to ND gradually restored PDH flux (8.40 ± 1.47% by Day 8) to control levels (8.69 ± 2.10%). Ex vivo NMR analysis of glutamate C4 showed reduced pyruvate contribution to acetyl-CoA during KD (4.1 ± 2.5%), which recovered upon reverting to ND (22.7 ± 1.82% vs. control: 27.6 ± 9.5%). Although PDK4 expression normalized, PDH activity remained partially impaired in the reverted group (36.80 ± 6.07 mmol NADH/min/mg) compared to controls (90.97 ± 5.40; P = 0.00007). CONCLUSION: KD-induced suppression of myocardial PDH flux is reversible, but its recovery requires significant time, with prolonged metabolic inflexibility persisting after transitioning to an ND. These findings highlight the value of in vivo assessment of cardiac PDH activity, complemented by conventional enzymatic analyses, to identify persistent metabolic inflexibility following ketogenic interventions.
Source: Cardiovascular Research
DOI: 10.1093/cvr/cvag053
Language: English
Topic: Diet and metabolism studies
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,329
Funders: Cancer Prevention and Research Institute of Texas, Muscular Dystrophy Association, University of Texas Southwestern Medical Center, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering, U.S. Army Medical Research Acquisition Activity
Awards: National Center for In Vivo Metabolism, G1740694830, A liquid helium-free preclinical polarizer for hyperpolarized 13C metabolic imaging, Pyruvate and acetate metabolism after TBI: implications for cerebral energy metabolism, G2650498737, G3502045362, North Texas Multimodal Small Animal Imaging Core Facility, A Clinical Polarizer for Carbon-13 (SpinLab), UT Southwestern NORC, Hyperpolarized MRI Technology Resource Center, Development of early metabolic imaging biomarkers for muscular dystrophy and cardiomyopathy in patients
OpenAlex ID: W7131679554