Division of Nutritional Sciences, University of Illinois at Urbana-ChampaignUrbana, IL United States; Dorothy M. Davis Heart and Lung Research Institute, Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
Division of Nutritional Sciences, University of Illinois at Urbana-ChampaignUrbana, IL United States.
J Nutr Biochem. 2021 May;91:108598. doi: 10.1016/j.jnutbio.2021.108598. Epub 2021 Feb 4.
Chronic metabolic diseases are on the rise worldwide and their etiology is multifactorial. Among them, inflammatory components like Tumor Necrosis Factor (TNF), contribute to whole-body metabolic impairment. Caloric Restriction (CR) combats metabolic diseases, but how it reduces inflammation remains understudied. We aimed to evaluate the impact of chronic CR on muscle inflammation, in particular TNF. In our study, 4-week old male Sprague-Dawley rats were fed a high-fat diet (HF, 45% Kcal of fat from lard) ad libitum for 3 months. After estimation of their energy requirement (1 month), they were then divided into three groups: HF ad libitum (OL), weight maintenance with AIN93M (9.5% Kcal from fat; ML, 100% of energy requirement), and caloric restriction (CR, AIN93M with 75% of energy requirement). This dietary intervention continued for six months. At this point, rats were sacrificed and gastrocnemius muscle was collected. CR induced a profound shift in fat and lean mass, and decreased growth factor IGF-1. Muscle qPCR analysis showed a marked decrease in inflammation and TNF (premRNA, mRNA, and protein) by CR, accompanied by Tnf promoter DNA hypermethylation. CR increased expression of histone deacetylase Sirt6 and decreased methyltransferase Suv39h1, together with decreased Tnf promoter and coding region binding of NF- κB and C/EBP-β. Following miRNA database mining, qPCR analysis revealed that CR downregulated the proinflammatory miR-19b and increased the anti-inflammatory miR-181a and its known targets. Chronic CR is able to regulate muscle-specific inflammation by targeting the NF-κB pathway as well as transcriptional and post-transcriptional regulation of Tnf gene.
慢性代谢性疾病在全球范围内呈上升趋势，其病因是多因素的。其中，肿瘤坏死因子（TNF）等炎症成分导致全身代谢受损。热量限制（CR）可对抗代谢性疾病，但它如何降低炎症仍有待研究。我们旨在评估慢性 CR 对肌肉炎症，特别是 TNF 的影响。在我们的研究中，4 周龄雄性 Sprague-Dawley 大鼠自由喂食高脂肪饮食（HF，45%的脂肪来自猪油）3 个月。在估计它们的能量需求（1 个月）后，它们被分为三组：HF 自由喂食（OL）、AIN93M 维持体重（9.5%的脂肪热量；ML，100%的能量需求）和热量限制（CR，AIN93M 能量需求的 75%）。这种饮食干预持续了六个月。此时，处死大鼠并收集腓肠肌。CR 导致脂肪和瘦体重发生深刻变化，并降低了生长因子 IGF-1。肌肉 qPCR 分析显示，CR 可显著降低炎症和 TNF（前体 RNA、mRNA 和蛋白质），同时 Tnf 启动子 DNA 超甲基化。CR 增加了组蛋白去乙酰化酶 Sirt6 的表达，降低了甲基转移酶 Suv39h1 的表达，同时减少了 NF-κB 和 C/EBP-β对 Tnf 启动子和编码区的结合。通过 miRNA 数据库挖掘后，qPCR 分析显示 CR 下调了促炎 miR-19b，增加了抗炎 miR-181a 及其已知靶标。慢性 CR 能够通过靶向 NF-κB 途径以及 Tnf 基因的转录和转录后调节来调节肌肉特异性炎症。
