FoxO Transcription Factors Are Critical Regulators of Diabetes-Related Muscle Atrophy
FoxO Transcription Factors Are Critical Regulators of Diabetes-Related Muscle Atrophy
复制标题
DOI：
10.2337/db18-0416
复制
发表时间：
2019-03-01
期刊：
影响因子：
7.7
通讯作者：
Kahn, C. Ronald
中科院分区：
文献类型：
--
作者：
O'Neill, Brian T.;Bhardwaj, Gourav;Kahn, C. Ronald
胰岛素缺乏和不受控制的糖尿病会导致分解代谢状态，导致肌肉力量下降，从而导致疾病相关的发病率。 FoxO 转录因子被胰岛素抑制，因此是胰岛素作用的关键介质。为了研究它们在糖尿病性肌肉萎缩中的作用，我们创建了肌肉特异性三重敲除 Fox01/3/4 的小鼠，并用链脲佐菌素 (STZ) 在这些 M-FoxO-TKO 小鼠中诱导糖尿病。由于泛素蛋白酶体降解和自噬改变增加，STZ 糖尿病小鼠的肌肉质量和肌纤维面积减少了 20-30%，其特征是含有 LC3 的囊泡增加，以及磷酸化 ULK1 和 LC3-II 水平升高。 STZ FoxO-TKO 小鼠的肌肉损失和降解/自噬增加的标记物都被完全阻止。转录组分析揭示了 STZ 糖尿病中泛素介导的蛋白水解途径中 FoxO 依赖性增加，包括 Fbxo32 (Atrogin1)、Trim63 (MuRF1)、Bnip3L 和 Gabarapl 的调节。短期胰岛素剥夺后，1 型糖尿病患者的肌肉中这些相同的基因增加了 1.4 至 3.3 倍。因此，FoxO 调节的基因在胰岛素缺乏型糖尿病中蛋白质降解增加和肌肉萎缩中发挥限速作用。
Insulin deficiency and uncontrolled diabetes lead to a catabolic state with decreased muscle strength, contributing to disease-related morbidity. FoxO transcription factors are suppressed by insulin and thus are key mediators of insulin action. To study their role in diabetic muscle wasting, we created mice with muscle-specific triple knockout of Fox01/3/4 and induced diabetes in these M-FoxO-TKO mice with streptozotocin (STZ). Muscle mass and myofiber area were decreased 20-30% in STZ-Diabetes mice due to increased ubiquitin-proteasome degradation and autophagy alterations, characterized by increased LC3-containing vesicles, and elevated levels of phosphorylated ULK1 and LC3-II. Both the muscle loss and markers of increased degradation/autophagy were completely prevented in STZ FoxO-TKO mice. Transcriptomic analyses revealed FoxO-dependent increases in ubiquitin-mediated proteolysis pathways in STZ-Diabetes, including regulation of Fbxo32 (Atrogin1), Trim63 (MuRF1), Bnip3L, and Gabarapl. These same genes were increased 1.4- to 3.3-fold in muscle from humans with type 1 diabetes after shortterm insulin deprivation. Thus, FoxO-regulated genes play a rate-limiting role in increased protein degradation and muscle atrophy in insulin-deficient diabetes.