The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China.
School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China.
Biochim Biophys Acta Mol Basis Dis. 2023 Apr;1869(4):166638. doi: 10.1016/j.bbadis.2023.166638. Epub 2023 Jan 16.
Atrial fibrillation (AF) is the most common tachyarrhythmia in urgent need of therapeutic optimization. Obesity engenders AF, and its pathogenesis is closely intertwined with insulin resistance (IR), but mechanism-based management is still underinvestigated. Intermittent fasting (IF) is a novel lifestyle intervention that mitigates IR, a potential AF driver, yet whether IF can prevent obesity-related AF remains elusive. Here, we aimed to evaluate the impacts of short-term IF on AF and to uncover the underlying mechanism.
We subjected obese mice (high-fat diet for 8-week) to IF (alternative-day fasting for another 5-week) for AF vulnerability and substrate formation assessment, and similarly treated neonatal atrial cardiomyocytes (NRCMs) and fibroblasts (NRCFs) (palmitate, 200 μM) with IF (alternative-day short-term starvation for 8-day) for mechanism investigation.
Obese mice were prone to AF and atrial remodeling. IF reduced AF inducibility, duration, and reversed atrial remodeling including channel disturbance, left atrial dilation, cardiac hypertrophy and fibrosis in obese mice independent of weight loss. Mechanistically, IF up-regulated the SIRT3 protein level both in vivo and in vitro, and pharmacologic inhibition (3-(1H-1,2,3-Triazol-4-yl) pyridine, 50 μM) and genetic suppression of SIRT3 could attenuate the IF-mediated benefits against hypertrophy and fibrosis. Furthermore, IF activated AMPK and Akt signaling, two positive downstream targets of SIRT3, and inactivated HIF1α signaling, a negative downstream target of SIRT3 in both obese mice atria and palmitate-treated cells, while inhibition of SIRT3 reversed these effects.
IF prevents obesity-related AF via SIRT3-mediated IR mitigation, thus representing a feasible lifestyle intervention to improve AF management.
心房颤动（AF）是最常见的需要治疗优化的快速性心律失常。肥胖会导致 AF，其发病机制与胰岛素抵抗（IR）密切相关，但基于机制的管理仍未得到充分研究。间歇性禁食（IF）是一种新的生活方式干预措施，可以减轻潜在的 AF 驱动因素 IR，但 IF 是否可以预防肥胖相关的 AF 仍不清楚。在这里，我们旨在评估短期 IF 对 AF 的影响，并揭示潜在的机制。
我们将肥胖小鼠（高脂饮食 8 周）进行 IF（隔日禁食再进行 5 周），以评估 AF 易感性和底物形成，并对同样用 IF（200 μM 软脂酸处理的乳鼠心房心肌细胞（NRCMs）和成纤维细胞（NRCFs））进行 IF（隔日短期饥饿 8 天）处理，以进行机制研究。
肥胖小鼠易发生 AF 和心房重构。IF 降低了肥胖小鼠的 AF 易感性、持续时间，并逆转了心房重构，包括通道紊乱、左心房扩张、心脏肥大和纤维化，而与体重减轻无关。在体内和体外，IF 均上调了 SIRT3 蛋白水平，药理学抑制（3-（1H-1,2,3-三唑-4-基）吡啶，50 μM）和 SIRT3 的遗传抑制均可减弱 IF 介导的对肥大和纤维化的益处。此外，IF 激活了 AMPK 和 Akt 信号通路，这是 SIRT3 的两个正向下游靶点，并抑制了 HIF1α 信号通路，这是 SIRT3 的一个负下游靶点，在肥胖小鼠心房和软脂酸处理的细胞中均如此，而 SIRT3 的抑制则逆转了这些效应。
IF 通过 SIRT3 介导的 IR 缓解预防肥胖相关的 AF，因此代表了一种可行的生活方式干预措施，可以改善 AF 的管理。
