Time-restricted feeding alleviates cardiac dysfunction induced by simulated microgravity via restoring cardiac FGF21 signaling
Time-restricted feeding alleviates cardiac dysfunction induced by simulated microgravity via restoring cardiac FGF21 signaling
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限时喂养通过恢复心脏 FGF21 信号传导缓解模拟微重力引起的心脏功能障碍
DOI：
10.1096/fj.202001246rr
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Li Jia
中科院分区：
文献类型：
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作者：
Wang Xin-Pei;Xing Chang-Yang;Zhang Jia-Xin;Zhou Jia-Heng;Li Yun-Chu;Yang Hong-Yan;Zhang Peng-Fei;Zhang Wei;Huang Yin;Long Jian-Gang;Gao Feng;Zhang Xing;Li Jia
饮食限制已被很好地描述为改善健康指标，但它是否有利于对极端环境（例如微重力）的病理生理适应仍是未知的。在这里，我们研究了在模拟微重力条件下，不减少热量摄入的每日禁食和喂养节奏对心功能和代谢的影响。雄性大鼠在自由进食或限时进食（TRF；每天进食时间限制为8小时）下进行后肢卸荷（HU）以模拟微重力。HU持续6周导致左室非同步化和心功能下降。HU还降低了丙酮酸脱氢酶（PDH）活性和心脏葡萄糖利用受损。所有这些大部分都被扶轮基金会保存下来。TRF对HU诱导的心肌质量损失没有影响，但显著改善心肌细胞的收缩功能。有趣的是，TRF提高了肝源性成纤维细胞生长因子21 （FGF21）水平，并增强了心脏FGF21信号传导，表现为FGF受体1 （FGFR1）表达上调及其下游标记物。在分离的心肌细胞中，FGF21治疗改善了PDH活性和葡萄糖利用，从而增强了细胞收缩功能。最后，FGF21的肝脏特异性敲低（KD）和心脏特异性FGFR1 KD均可消除TRF在HU大鼠中的心脏保护作用。这些数据表明，TRF通过恢复心脏FGF21信号，至少在一定程度上改善了模拟微重力诱导的心脏葡萄糖利用和心功能障碍，表明TRF可能是长期太空飞行中心脏保护的潜在对策。
Dietary restriction has been well‐described to improve health metrics, but whether it could benefit pathophysiological adaptation to extreme environment, for example, microgravity, remains unknown. Here, we investigated the effects of a daily rhythm of fasting and feeding without reducing caloric intake on cardiac function and metabolism against simulated microgravity. Male rats under ad libitum feeding or time‐restricted feeding (TRF; food access limited to 8 hours every day) were subjected to hindlimb unloading (HU) to simulate microgravity. HU for 6 weeks led to left ventricular dyssynchrony and declined cardiac function. HU also lowered pyruvate dehydrogenase (PDH) activity and impaired glucose utilization in the heart. All these were largely preserved by TRF. TRF showed no effects on HU‐induced loss of cardiac mass, but significantly improved contractile function of cardiomyocytes. Interestingly, TRF raised liver‐derived fibroblast growth factor 21 (FGF21) level and enhanced cardiac FGF21 signaling as manifested by upregulation of FGF receptor‐1 (FGFR1) expression and its downstream markers in HU rats. In isolated cardiomyocytes, FGF21 treatment improved PDH activity and glucose utilization, consequently enhancing cell contractile function. Finally, both liver‐specific knockdown (KD) of FGF21 and cardiac‐specific FGFR1 KD abrogated the cardioprotective effects of TRF in HU rats. These data demonstrate that TRF improves cardiac glucose utilization and ameliorates cardiac dysfunction induced by simulated microgravity, at least partially, through restoring cardiac FGF21 signaling, suggesting TRF as a potential countermeasure for cardioprotection in long‐term spaceflight.