Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, United States.
Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States.
Front Endocrinol (Lausanne). 2024 Sep 24;15:1325286. doi: 10.3389/fendo.2024.1325286. eCollection 2024.
Reducing Optic Atrophy 1 (OPA1) expression in skeletal muscle in male mice induces Activation Transcription Factor 4 (ATF4) and the integrated stress response (ISR). Additionally, skeletal muscle secretion of Fibroblast Growth Factor 21 (FGF21) is increased, which mediates metabolic adaptations including resistance to diet-induced obesity (DIO) and glucose intolerance in these mice. Although FGF21 induction in this model can be reversed with pharmacological attenuation of ER stress, it remains to be determined if ATF4 is responsible for FGF21 induction and its metabolic benefits in this model.
We generated mice with homozygous floxed and alleles and a tamoxifen-inducible Cre transgene controlled by the human skeletal actin promoter to enable simultaneous depletion of OPA1 and ATF4 in skeletal muscle (mAO DKO). Mice were fed high fat (HFD) or control diet and evaluated for ISR activation, body mass, fat mass, glucose tolerance, insulin tolerance and circulating concentrations of FGF21 and growth differentiation factor 15 (GDF15).
In mAO DKO mice, ATF4 induction is absent. Other indices of ISR activation, including XBP1s, ATF6, and CHOP were induced in mAO DKO males, but not in mOPA1 or mAO DKO females. Resistance to diet-induced obesity was not reversed in mAO DKO mice of both sexes. Circulating FGF21 and GDF15 illustrated sexually dimorphic patterns. Loss of OPA1 in skeletal muscle increases circulating FGF21 in mOPA1 males, but not in mOPA1 females. Additional loss of ATF4 decreased circulating FGF21 in mAO DKO male mice, but increased circulating FGF21 in female mAO DKO mice. Conversely, circulating GDF15 was increased in mAO DKO males and mOPA1 females, but not in mAO DKO females.
Sex differences exist in the transcriptional outputs of the ISR following OPA deletion in skeletal muscle. Deletion of ATF4 in male and female OPA1 KO mice does not reverse the resistance to DIO. Induction of circulating FGF21 is ATF4 dependent in males, whereas induction of circulating GDF15 is ATF4 dependent in females. Elevated GDF15 in males and FGF21 in females could reflect activation by other transcriptional outputs of the ISR, that maintain mitokine-dependent metabolic protection in an ATF4-independent manner.
在雄性小鼠的骨骼肌中降低视神经萎缩 1 型（OPA1）的表达会诱导激活转录因子 4（ATF4）和整合应激反应（ISR）。此外，成纤维细胞生长因子 21（FGF21）的骨骼肌分泌增加，介导包括抵抗饮食诱导肥胖（DIO）和葡萄糖耐量受损在内的代谢适应。尽管在该模型中，通过抑制内质网应激的药理学作用可以逆转 FGF21 的诱导，但仍需要确定 ATF4 是否负责该模型中 FGF21 的诱导及其代谢益处。
我们生成了具有纯合 floxed 和 等位基因和由人骨骼肌肌动蛋白启动子控制的可诱导 Cre 转基因的小鼠，以实现骨骼肌中 OPA1 和 ATF4 的同时耗竭（mAO DKO）。小鼠喂食高脂肪（HFD）或对照饮食，并评估 ISR 激活、体重、脂肪量、葡萄糖耐量、胰岛素耐量以及成纤维细胞生长因子 21（FGF21）和生长分化因子 15（GDF15）的循环浓度。
在 mAO DKO 小鼠中，ATF4 的诱导不存在。其他 ISR 激活指标，包括 XBP1s、ATF6 和 CHOP，在 mAO DKO 雄性小鼠中被诱导，但在 mOPA1 或 mAO DKO 雌性小鼠中未被诱导。雌雄两性 mAO DKO 小鼠均未逆转饮食诱导的肥胖。循环 FGF21 和 GDF15 呈现出性别二态模式。骨骼肌中 OPA1 的缺失增加了 mOPA1 雄性小鼠的循环 FGF21，但不增加 mOPA1 雌性小鼠的循环 FGF21。在 mAO DKO 雄性小鼠中，ATF4 的进一步缺失降低了循环 FGF21，但增加了雌性 mAO DKO 小鼠的循环 FGF21。相反，循环 GDF15 在 mAO DKO 雄性小鼠和 mOPA1 雌性小鼠中增加，但在 mAO DKO 雌性小鼠中不增加。
在骨骼肌中 OPA 缺失后，ISR 的转录输出存在性别差异。在雄性和雌性 OPA1 KO 小鼠中缺失 ATF4 并不能逆转 DIO 的抵抗。循环 FGF21 的诱导依赖于 ATF4，而循环 GDF15 的诱导依赖于 ATF4 在雌性小鼠中。雄性中升高的 GDF15 和雌性中升高的 FGF21 可能反映了 ISR 的其他转录输出的激活，以一种 ATF4 不依赖的方式维持了促线粒体代谢保护。
