ArticlePhysiological reports2023
Downregulation of extramitochondrial BCKDH and its uncoupling from AMP deaminase in type 2 diabetic OLETF rat hearts.
Article in Physiological reports, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 14 citations in OpenAlex.
- Article
- Lipid droplets beyond storage: Cellular metabolic modulator in the diabetic heart (Review).International journal of molecular medicine · 2026Review
- Multimodal Therapeutic Strategies Targeting BCAA Metabolism in Diabetic Cardiomyopathy: A Path to Cardioprotection.Cardiovascular toxicology · 2025Review
- A Molecular Perspective on the Intricate Interplay Among Exosomes, Bioenergetic Metabolism, and the Pathogenesis of Diabetic Cardiomyopathy.Journal of cardiovascular translational research · 2025Review
- Metformin alleviates diastolic dysfunction in mice with experimental diabetic cardiomyopathy.Journal of molecular and cellular cardiology plus · 2025Article
- Gut Microbiota-Derived Metabolites Orchestrate Metabolic Reprogramming in Diabetic Cardiomyopathy: Mechanisms and Therapeutic Frontiers.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Review
- Emerging Insights into the Relationship Between Amino Acid Metabolism and Diabetic Cardiomyopathy.Biomolecules · 2025Review
- Impaired cardiac branched-chain amino acid metabolism in a novel model of diabetic cardiomyopathy.Cardiovascular diabetology · 2025Article
- Role of AMP deaminase in diabetic cardiomyopathy.Molecular and cellular biochemistry · 2024Review
- Redefining Diabetic Cardiomyopathy: Perturbations in Substrate Metabolism at the Heart of Its Pathology.Diabetes · 2024Review
- Disruption of BCAA degradation is a critical characteristic of diabetic cardiomyopathy revealed by integrated transcriptome and metabolome analysis.Open life sciences · 2024Article
- Amino acid metabolism in health and disease.Signal transduction and targeted therapy · 2023Review
- Downregulation of extramitochondrial BCKDH and its uncoupling from AMP deaminase in type 2 diabetic OLETF rat hearts.Physiological reports · 2023Article
- Identification and analysis of hub genes of hypoxia-immunity in type 2 diabetes mellitus.Frontiers in genetics · 2023Article
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Authors and funding
15 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Systemic branched-chain amino acid (BCAA) metabolism is dysregulated in cardiometabolic diseases. We previously demonstrated that upregulated AMP deaminase 3 (AMPD3) impairs cardiac energetics in a rat model of obese type 2 diabetes, Otsuka Long-Evans-Tokushima fatty (OLETF). Here, we hypothesized that the cardiac BCAA levels and the activity of branched-chain α-keto acid dehydrogenase (BCKDH), a rate-limiting enzyme in BCAA metabolism, are altered by type 2 diabetes (T2DM), and that upregulated AMPD3 expression is involved in the alteration. Performing proteomic analysis combined with immunoblotting, we discovered that BCKDH localizes not only to mitochondria but also to the endoplasmic reticulum (ER), where it interacts with AMPD3. Knocking down AMPD3 in neonatal rat cardiomyocytes (NRCMs) increased BCKDH activity, suggesting that AMPD3 negatively regulates BCKDH. Compared with control rats (Long-Evans Tokushima Otsuka [LETO] rats), OLETF rats exhibited 49% higher cardiac BCAA levels and 49% lower BCKDH activity. In the cardiac ER of the OLETF rats, BCKDH-E1α subunit expression was downregulated, while AMPD3 expression was upregulated, resulting in an 80% lower AMPD3-E1α interaction compared to LETO rats. Knocking down E1α expression in NRCMs upregulated AMPD3 expression and recapitulated the imbalanced AMPD3-BCKDH expressions observed in OLETF rat hearts. E1α knockdown in NRCMs inhibited glucose oxidation in response to insulin, palmitate oxidation, and lipid droplet biogenesis under oleate loading. Collectively, these data revealed previously unrecognized extramitochondrial localization of BCKDH in the heart and its reciprocal regulation with AMPD3 and imbalanced AMPD3-BCKDH interactions in OLETF. Downregulation of BCKDH in cardiomyocytes induced profound metabolic changes that are observed in OLETF hearts, providing insight into mechanisms contributing to the development of diabetic cardiomyopathy.
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