Downregulation of extramitochondrial <scp>BCKDH</scp> and its uncoupling from <scp>AMP</scp> deaminase in type 2 diabetic <scp>OLETF</scp> rat hearts

Ogawa, Toshifumi; Kouzu, Hidemichi; Osanami, Arata; Tatekoshi, Yuki; Sato, Tatsuya; Kuno, Atsushi; Fujita, Yugo; Ino, Shoya; Shimizu, Masaki; Toda, Yuki; Ohwada, Wataru; Yano, Toshiyuki; Tanno, Masaya; Miki, Takayuki; Miura, Tetsuji

doi:10.14814/phy2.15608

Cited by 4 publications

(4 citation statements)

References 62 publications

(122 reference statements)

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“…However, both have been comparatively understudied in the diabetic heart versus fatty acid and carbohydrate metabolism, while myocardial amino acid metabolism in general has been ignored. Nonetheless, it has been reported that branched chain α-ketoacid CoA dehydrogenase protein expression is decreased in hearts from genetically obese rats, suggestive of an impairment in myocardial branched chain amino acid metabolism ( 54 ).…”

Section: Cardiac Substrate Metabolism Perturbations In Dbcmmentioning

confidence: 99%

Redefining Diabetic Cardiomyopathy: Perturbations in Substrate Metabolism at the Heart of Its Pathology

Heather,

Gopal,

Srnic

et al. 2024

Diabetes

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Cardiovascular disease represents the leading cause of death in people with diabetes, most notably from macrovascular diseases such as myocardial infarction or heart failure. Diabetes also increases the risk of a specific form of cardiomyopathy referred to as diabetic cardiomyopathy (DbCM), originally defined as ventricular dysfunction in the absence of underlying coronary artery disease and/or hypertension. Herein, we provide an overview on the key mediators of DbCM, with an emphasis on the role for perturbations in cardiac substrate metabolism. We discuss key mechanisms regulating metabolic dysfunction in DbCM, with additional focus on the role of metabolites as signalling molecules within the diabetic heart. Furthermore, we discuss the preclinical approaches to target these perturbations to alleviate DbCM. With several advancements in our understanding, we propose “diastolic dysfunction in the presence of altered myocardial metabolism in a person with diabetes, but absence of other known causes of cardiomyopathy and/or hypertension”, as a new definition for, or approach to classify, DbCM. However, we recognize that no definition can fully explain the complexity of why some individuals with DbCM exhibit diastolic dysfunction, whereas others develop systolic dysfunction. Due to DbCM sharing pathological features with heart failure with preserved ejection fraction (HFpEF), the latter of which is more prevalent in the diabetic population, it is imperative to determine whether effective management of DbCM decreases HFpEF prevalence.

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Section: Cardiac Substrate Metabolism Perturbations In Dbcmmentioning

confidence: 99%

Redefining Diabetic Cardiomyopathy: Perturbations in Substrate Metabolism at the Heart of Its Pathology

Heather,

Gopal,

Srnic

et al. 2024

Diabetes

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“…This portion of BCKDH is present on the endoplasmic reticulum (ER) and interacts with AMP deaminase 3 (AMPD3), and is negatively regulated by AMPD3. 72 Upregulation of AMPD3 has been reported to impair energy metabolism in OLETF hearts. This study further suggested that AMPD3 may induce cardiometabolic changes through AMPD3-BCKDH expression imbalance in cardiomyocytes of diabetic individuals, providing new insights into the mechanism of the development of this disease.…”

Section: Branched-chain Amino Acids (Bcaas)mentioning

confidence: 99%

Section: Bcaas In Diseasementioning

confidence: 99%

“…55,59 BCAA metabolism is equally important for the function of proinflammatory CD4 + and CD8 + T cells and immunosuppressive regulatory Treg cells, 41,[265][266][267][268][269][270][271][272] which plays key role in metabolic diseases, liver and kidney diseases. 10,11,[65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84]345,346 Currently, drugs targeting BCAA uptakedependent amino acid transporter LAT1 metabolic enzymes BCAT and BCKDK are in trials. [317][318][319][320][321]347 Aspartate is a nonessential amino acid, but it is also an intrinsic limiting factor in the growth of some tumors.…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

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Amino acid metabolism in health and disease

Ling,

Jiang,

et al. 2023

Sig Transduct Target Ther

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Amino acids are the building blocks of protein synthesis. They are structural elements and energy sources of cells necessary for normal cell growth, differentiation and function. Amino acid metabolism disorders have been linked with a number of pathological conditions, including metabolic diseases, cardiovascular diseases, immune diseases, and cancer. In the case of tumors, alterations in amino acid metabolism can be used not only as clinical indicators of cancer progression but also as therapeutic strategies. Since the growth and development of tumors depend on the intake of foreign amino acids, more and more studies have targeted the metabolism of tumor-related amino acids to selectively kill tumor cells. Furthermore, immune-related studies have confirmed that amino acid metabolism regulates the function of effector T cells and regulatory T cells, affecting the function of immune cells. Therefore, studying amino acid metabolism associated with disease and identifying targets in amino acid metabolic pathways may be helpful for disease treatment. This article mainly focuses on the research of amino acid metabolism in tumor-oriented diseases, and reviews the research and clinical research progress of metabolic diseases, cardiovascular diseases and immune-related diseases related to amino acid metabolism, in order to provide theoretical basis for targeted therapy of amino acid metabolism.

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