| Content Provider | Springer Nature : BioMed Central |
|---|---|
| Author | Asakura, Junko Nagao, Manabu Shinohara, Masakazu Hosooka, Tetsuya Kuwahara, Naoya Nishimori, Makoto Tanaka, Hidekazu Satomi-Kobayashi, Seimi Matsui, Sho Sasaki, Tsutomu Kitamura, Tadahiro Otake, Hiromasa Ishida, Tatsuro Ogawa, Wataru Hirata, Ken-Ichi Toh, Ryuji |
| Abstract | Background Systemic insulin resistance plays an important role in the pathogenesis of type 2 diabetes and its complications. Although impaired branched-chain amino acid (BCAA) metabolism has been reported to be involved in the development of diabetes, the relationship between cardiac BCAA metabolism and the pathogenesis of diabetic cardiomyopathy (DbCM) remains unclear. Objectives The aim of this study was to investigate BCAA metabolism in insulin-resistant hearts by using a novel mouse model of DbCM. Methods The cardiac phenotypes of adipocyte-specific 3′-phosphoinositide–dependent kinase 1 (PDK1)-deficient (A-PDK1KO) mice were assessed by histological analysis and echocardiography. The metabolic characteristics and cardiac gene expression were determined by mass spectrometry or RNA sequencing, respectively. Cardiac protein expression was evaluated by Western blot analysis. Results A-PDK1KO mouse hearts exhibited hypertrophy with prominent insulin resistance, consistent with cardiac phenotypes and metabolic disturbances previously reported as DbCM characteristics. RNA sequencing revealed the activation of BCAA uptake in diabetic hearts. In addition, the key enzymes involved in cardiac BCAA catabolism were downregulated at the protein level in A-PDK1KO mice, leading to the accumulation of BCAAs in the heart. Mechanistically, the accumulation of the BCAA leucine caused cardiac hypertrophy via the activation of mammalian target of rapamycin complex 1 (mTORC1). Conclusions A-PDK1KO mice closely mimic the cardiac phenotypes and metabolic alterations observed in human DbCM and exhibit impaired BCAA metabolism in the heart. This model may contribute to a better understanding of DbCM pathophysiology and to the development of novel therapies for this disease. |
| Related Links | https://cardiab.biomedcentral.com/counter/pdf/10.1186/s12933-025-02725-5.pdf |
| Ending Page | 13 |
| Page Count | 13 |
| Starting Page | 1 |
| File Format | HTM / HTML |
| ISSN | 14752840 |
| DOI | 10.1186/s12933-025-02725-5 |
| Journal | Cardiovascular Diabetology |
| Issue Number | 1 |
| Volume Number | 24 |
| Language | English |
| Publisher | BioMed Central |
| Publisher Date | 2025-04-16 |
| Access Restriction | Open |
| Subject Keyword | Diabetes Angiology Cardiology Diabetic cardiomyopathy Branched-chain amino acid Heart failure Diabetes mellitus Cardiac metabolism |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cardiology and Cardiovascular Medicine Internal Medicine Endocrinology, Diabetes and Metabolism |
| Journal Impact Factor | 8.5/2023 |
| 5-Year Journal Impact Factor | 8.9/2023 |
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