Academic Journal
Systemic Metabolic Rewiring in a Mouse Model of Left Ventricular Hypertrophy.
| Τίτλος: | Systemic Metabolic Rewiring in a Mouse Model of Left Ventricular Hypertrophy. |
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| Συγγραφείς: | Schmidt AV; Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA., Thambidurai T; Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA., D'Annibale O; Biochemical Genetics Laboratory, Children's Hospital of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.; Section of Clinical and Genetics Metabolism, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.; Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Bharathi SS; Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USA., Wood T; Biochemical Genetics Laboratory, Children's Hospital of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.; Section of Clinical and Genetics Metabolism, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA., Goetzman ES; Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USA., Stelzer JE; Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. |
| Πηγή: | International journal of molecular sciences [Int J Mol Sci] 2025 Oct 17; Vol. 26 (20). Date of Electronic Publication: 2025 Oct 17. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Basel, Switzerland : MDPI, [2000- |
| Ιατρικοί όροι (MeSH): | Hypertrophy, Left Ventricular*/metabolism , Hypertrophy, Left Ventricular*/pathology , Hypertrophy, Left Ventricular*/genetics, Fatty Acids/metabolism ; Myocardium/metabolism ; Muscle, Skeletal/metabolism ; Mitochondria/metabolism ; Animals ; Mice ; Disease Models, Animal ; Lipid Metabolism ; Male ; Energy Metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Oxidative Phosphorylation |
| Περίληψη: | Left ventricular hypertrophy (LVH) refers to the pathological thickening of the myocardial wall and is strongly associated with several adverse cardiac outcomes and sudden cardiac death. While the biomechanical drivers of LVH are well established, growing evidence points to a critical role for cardiac and systemic metabolism in modulating hypertrophic remodeling and disease pathogenesis. Despite the efficiency of fatty acid oxidation (FAO), LVH hearts preferentially increase glucose uptake and catabolism to drive glycolysis and oxidative phosphorylation (OXPHOS). The development of therapies to increase and enhance LFCA FAO is underway, with promising results. However, the mechanisms of systemic metabolic states and LCFA dynamics in the context of cardiac hypertrophy remain incompletely understood. Further, it is unknown to what extent cardiac metabolism is influenced by whole-body energy balance and lipid profiles, despite the common occurrence of lipotoxicity in LVH. In this study, we measured whole-body and cellular respiration along with analysis of lipid and glycogen stores in a mouse model of LVH. We found that loss of the cardiac-specific gene, myosin-binding protein C3 (Mybpc3), resulted in depletion of adipose tissue, decreased mitochondrial function in skeletal muscle, increased lipid accumulation in both the heart and liver, and loss of whole-body metabolic flux. We found that supplementation of exogenous LCFAs boosted LVH mitochondrial function and reversed cardiac lipid accumulation but did not fully reverse the hypertrophied heart nor systemic metabolic phenotypes. This study indicates that the LVH phenotype caused systemic metabolic rewiring in Mybpc3-/- mice and that exogenous LCFA supplementation boosted mitochondrial function in both cardiac and skeletal muscle. |
| References: | Methods Mol Biol. 2018;1782:31-70. (PMID: 29850993) Circ Res. 2017 Sep 15;121(7):749-770. (PMID: 28912181) Redox Biol. 2024 Jul;73:103184. (PMID: 38718533) Nutrients. 2020 Aug 13;12(8):. (PMID: 32823643) Heart Fail Rev. 2013 Sep;18(5):607-22. (PMID: 22948484) Circulation. 2012 Oct 2;126(14):1705-16. (PMID: 22932257) J Nutr. 2003 Feb;133(2):358-61. (PMID: 12566467) Front Physiol. 2022 Feb 25;13:831829. (PMID: 35283773) Biomolecules. 2024 Sep 15;14(9):. (PMID: 39334926) Methods Mol Biol. 2023;2675:77-96. (PMID: 37258757) Free Radic Res. 2011 Jan;45(1):29-36. (PMID: 21110783) Circ Res. 2021 May 14;128(10):1487-1513. (PMID: 33983836) Cardiovasc Res. 2004 Aug 1;63(2):293-304. (PMID: 15249187) Rev Endocr Metab Disord. 2020 Dec;21(4):479-493. (PMID: 32654032) Acta Physiol Scand. 1977 Nov;101(3):318-28. (PMID: 202144) JACC Heart Fail. 2018 Jan;6(1):1-7. (PMID: 29284577) Basic Res Cardiol. 2020 Aug 3;115(5):53. (PMID: 32748289) Circulation. 2021 Nov 23;144(21):1714-1731. (PMID: 34672721) Front Neurosci. 2020 Jul 07;14:531. (PMID: 32733181) Exp Cell Res. 2017 Nov 1;360(1):12-18. (PMID: 28344054) Front Physiol. 2022 Jul 04;13:946474. (PMID: 35860662) Science. 2006 May 5;312(5774):734-7. (PMID: 16675698) Nat Metab. 2021 Sep;3(9):1134-1136. (PMID: 34489606) Pediatr Res. 2007 Mar;61(3):301-6. (PMID: 17314687) Cardiovasc Res. 2024 Feb 17;119(18):2884-2901. (PMID: 38252923) Nutr Clin Pract. 2004 Oct;19(5):447-54. (PMID: 16215138) Br J Nutr. 1980 Jan;43(1):83-6. (PMID: 7370219) Sci Rep. 2017 Dec 13;7(1):17528. (PMID: 29235526) Am J Cardiovasc Drugs. 2004;4(4):201-9. (PMID: 15285695) Int J Mol Sci. 2024 May 28;25(11):. (PMID: 38892064) FASEB J. 2004 Nov;18(14):1692-700. (PMID: 15522914) Am J Physiol Endocrinol Metab. 2000 Dec;279(6):E1325-34. (PMID: 11093921) Curr Med Chem. 2012;19(26):4511-22. (PMID: 22934775) Curr Hypertens Rep. 2020 Feb 3;22(2):11. (PMID: 32016791) Circulation. 2023 Dec 5;148(23):1870-1886. (PMID: 37886847) Circ Res. 2025 May 23;136(11):1306-1334. (PMID: 40403103) Anal Bioanal Chem. 2012 Aug;404(3):741-51. (PMID: 22766757) Am J Physiol Cell Physiol. 2024 Sep 1;327(3):C728-C736. (PMID: 39069824) J Mol Cell Cardiol. 2020 Jul;144:24-34. (PMID: 32418915) Eur Heart J. 2016 Mar 21;37(12):942-54. (PMID: 26508169) EMBO Mol Med. 2014 Apr;6(4):482-95. (PMID: 24567073) Circulation. 2014 Nov 11;130(20):1790-9. (PMID: 25266948) Circulation. 2010 Oct 19;122(16):1562-9. (PMID: 20921440) Circ Res. 2002 Mar 22;90(5):594-601. (PMID: 11909824) Am J Physiol Heart Circ Physiol. 2017 Feb 1;312(2):H305-H313. (PMID: 28011586) J Cell Mol Med. 2012 Sep;16(9):2022-34. (PMID: 22129453) |
| Grant Information: | R01 HL175803 United States HL NHLBI NIH HHS; R01 HL146676 United States HL NHLBI NIH HHS; R01 HL173989 United States HL NHLBI NIH HHS; 5R01HL153236-04 United States NH NIH HHS; 961478 United States AHA American Heart Association-American Stroke Association; R01 HL153236 United States HL NHLBI NIH HHS; 1R01HL175803-01A1 United States NH NIH HHS; 5R01HL173989-02 United States NH NIH HHS |
| Contributed Indexing: | Keywords: cardiac lipotoxicity; cardiac myosin-binding protein C; left ventricular hypertrophy; long-chain fatty acid; systemic metabolism |
| Substance Nomenclature: | 0 (Fatty Acids) |
| Entry Date(s): | Date Created: 20251029 Date Completed: 20251029 Latest Revision: 20260307 |
| Update Code: | 20260307 |
| PubMed Central ID: | PMC12562477 |
| DOI: | 10.3390/ijms262010111 |
| PMID: | 41155405 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1422-0067 |
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| DOI: | 10.3390/ijms262010111 |