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首页> 外文期刊>Journal of Cachexia, Sarcopenia and Muscle >Fatty acid-binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia-inducible factor 1 in mice
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Fatty acid-binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia-inducible factor 1 in mice

机译：脂肪酸结合蛋白4通过缺氧诱导因子1调节小鼠肩袖撕裂后的脂肪浸润

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Abstract Background Fatty infiltration in skeletal muscle is directly linked to loss of muscle strength and is associated with various adverse physical outcomes such as muscle atrophy, inflammation, insulin resistance, mobility impairments, and even mortality in the elderly. Aging, mechanical unloading, muscle injury, and hormonal imbalance are main causes of muscle fat accumulation, and the fat cells are derived from muscle stem cells via adipogenic differentiation. However, the pathogenesis and molecular mechanisms of fatty infiltration in muscles are still not fully defined. Fatty acid-binding protein 4 (FABP4) is a carrier protein for fatty acids and is involved in fatty acid uptake, transport, and lipid metabolism. Rotator cuff tear (RCT) usually occurs in the elderly and is closely related with fatty infiltration in injured muscle. To investigate potential mechanisms for fatty infiltration other than adipogenic differentiation of muscle stem cells, we examined the role of FABP4 in muscle fatty infiltration in an RCT mouse model. Methods In the RCT model, we evaluated the expression of FABP4 by qRT-PCR, western blotting, and immunohistochemical analyses. Histological changes such as inflammation and fat accumulation in the injured muscles were examined immunohistochemically. To evaluate whether hypoxia induces FABP4 expression, the levels of FABP4 mRNA and protein in C3H10T1/2 cells after hypoxia were examined. Using a transient transfection assay in 293T cells, we assessed the promoter activity of FABP4 by hypoxia-inducible factors (HIFs). Additionally, we evaluated the reduction in FABP4 expression and fat accumulation using specific inhibitors for HIF1 and FABP4, respectively. Results FABP4 expression was significantly increased after RCT in mice, and its expression was localized in the intramuscular fatty region. Rotator cuff tear-induced FABP4 expression was up-regulated by hypoxia. HIF1???±, which is activated by hypoxia, augmented the promoter activity of FABP4, together with HIF1???2. Hypoxia-induced FABP4 expression was significantly decreased by HIF1 inhibitor treatment. Furthermore, in RCT model mice, fat accumulation was remarkably reduced by FABP4 inhibitor treatment. Conclusions This study shows that RCT induces FABP4 expression, leading to fat accumulation in injured muscle. FABP4 transcription is regulated by the direct binding of HIF1 to the FABP4 promoter in the hypoxic condition induced by RCT. Fat accumulation in injured muscle was reduced by the inhibition of FABP4. Ultimately, in the RCT model, we identified a novel mechanism for fatty infiltration by FABP4, which differs from adipogenic differentiation of muscle stem cells, and we found that fatty infiltration might be regulated by inhibition of HIF1 or FABP4.
机译：摘要背景骨骼肌中的脂肪浸润与肌肉力量的丧失直接相关，并与各种不良的身体状况有关，例如肌肉萎缩，炎症，胰岛素抵抗，活动能力减退，甚至是老年人的死亡率。衰老，机械负荷减轻，肌肉损伤和荷尔蒙失调是肌肉脂肪积聚的主要原因，并且脂肪细胞通过成脂分化从肌肉干细胞衍生而来。但是，肌肉中脂肪浸润的发病机理和分子机制仍未完全确定。脂肪酸结合蛋白4（FABP4）是脂肪酸的载体蛋白，参与脂肪酸的摄取，转运和脂质代谢。肩袖撕裂（RCT）通常发生在老年人中，并且与受伤肌肉中的脂肪浸润密切相关。为了研究脂肪浸润的潜在机制，而不是脂肪干分化的肌肉干细胞，我们检查了RCP小鼠模型中FABP4在肌肉脂肪浸润中的作用。方法在RCT模型中，我们通过qRT-PCR，蛋白质印迹和免疫组化分析评估了FABP4的表达。免疫组织化学检查了组织学变化，例如炎症和受伤肌肉中脂肪的积聚。为了评估缺氧是否诱导FABP4表达，研究了缺氧后C3H10T1 / 2细胞中FABP4 mRNA和蛋白的水平。在293T细胞中使用瞬时转染测定，我们通过缺氧诱导因子（HIF）评估了FABP4的启动子活性。此外，我们分别使用HIF1和FABP4的特异性抑制剂评估了FABP4表达的减少和脂肪积累。结果小鼠RCT后FABP4表达显着增加，其表达位于肌内脂肪区。缺氧上调了肩袖撕裂诱导的FABP4表达。通过缺氧激活的HIF1 + +与HIF1-2一起增强了FABP4的启动子活性。低氧诱导的FABP4表达通过HIF1抑制剂治疗显着降低。此外，在RCT模型小鼠中，通过FABP4抑制剂治疗显着减少了脂肪积累。结论该研究表明，RCT诱导FABP4表达，导致受伤肌肉中脂肪堆积。在RCT诱导的低氧条件下，HIF1与FABP4启动子的直接结合可调节FABP4的转录。通过抑制FABP4减少了受伤肌肉中的脂肪积累。最终，在RCT模型中，我们确定了FABP4引起脂肪浸润的新机制，这不同于肌肉干细胞的成脂分化，并且我们发现脂肪浸润可能受HIF1或FABP4抑制的调节。

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