TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, China.
TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, China; Institute of Myocardial Injury and Repair, Wuhan University, Wuhan, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, China.
Biochim Biophys Acta Mol Basis Dis. 2024 Oct;1870(7):167442. doi: 10.1016/j.bbadis.2024.167442. Epub 2024 Jul 24.
Unlike humans and other mammals, zebrafish demonstrate a remarkable capacity to regenerate their injured hearts throughout life. Mitochondrial fatty acid β-oxidation (FAO) contributes to major energy demands of the adult hearts under physiological conditions; however, its functions in regulating cardiac regeneration and the underlying mechanisms are not completely understood. Different strategies targeting FAO have yield mixed outcomes. Here, we demonstrated that pharmacological inhibition of mitochondrial FAO with mildronate (MD) caused lipid accumulation in zebrafish larvae and suppressed ventricle regeneration. MD treatment impeded cardiogenic factor reactivation and cardiomyocyte (CM) proliferation, and impaired ventricle regeneration could be rescued by exogenous l-carnitine supplementation. Moreover, compared with the ablated hearts of wild-type fish, ventricle regeneration, cardiogenic factor reactivation and CM proliferation were significantly blocked in the ablated hearts of carnitine palmitoyltransferase-1b (cpt1b) knockout zebrafish. Further experiments suggested that NF-κB signaling and increased inflammation may be involved in the impediment of ventricle regeneration caused by systemic mitochondrial FAO inhibition. Overall, our study demonstrates the essential roles of mitochondrial FAO in zebrafish ventricle regeneration and reaffirms the sophisticated and multifaceted roles of FAO in heart regeneration with regard to different injury models and means of FAO inhibition.
与人类和其他哺乳动物不同，斑马鱼在其整个生命周期中都表现出非凡的心脏再生能力。线粒体脂肪酸β-氧化（FAO）有助于在生理条件下满足成年心脏的主要能量需求；然而，其在调节心脏再生和潜在机制中的功能尚不完全清楚。针对 FAO 的不同策略产生了不同的结果。在这里，我们证明了使用米力农（MD）抑制线粒体 FAO 的药理学方法会导致斑马鱼幼虫中的脂质积累并抑制心室再生。MD 处理抑制了心脏生成因子的重新激活和心肌细胞（CM）的增殖，并且可以通过外源性左旋肉碱补充来挽救心室再生的缺陷。此外，与野生型鱼的消融心脏相比，肉碱棕榈酰转移酶-1b（cpt1b）敲除斑马鱼的消融心脏中的心室再生、心脏生成因子的重新激活和 CM 的增殖显著受到抑制。进一步的实验表明，NF-κB 信号和炎症增加可能参与了系统性线粒体 FAO 抑制引起的心室再生障碍。总的来说，我们的研究表明线粒体 FAO 在斑马鱼心室再生中的重要作用，并再次证实了 FAO 在不同损伤模型和 FAO 抑制手段下对心脏再生的复杂和多方面作用。
