Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Cell Metab. 2013 Sep 3;18(3):368-79. doi: 10.1016/j.cmet.2013.07.012.
Catabolic conditions like chronic kidney disease (CKD) cause loss of muscle mass by unclear mechanisms. In muscle biopsies from CKD patients, we found activated Stat3 (p-Stat3) and hypothesized that p-Stat3 initiates muscle wasting. We created mice with muscle-specific knockout (KO) that prevents activation of Stat3. In these mice, losses of body and muscle weights were suppressed in models with CKD or acute diabetes. A small-molecule that inhibits Stat3 activation produced similar responses, suggesting a potential for translation strategies. Using CCAAT/enhancer-binding protein δ (C/EBPδ) KO mice and C2C12 myotubes with knockdown of C/EBPδ or myostatin, we determined that p-Stat3 initiates muscle wasting via C/EBPδ, stimulating myostatin, a negative muscle growth regulator. C/EBPδ KO also improved survival of CKD mice. We verified that p-Stat3, C/EBPδ, and myostatin were increased in muscles of CKD patients. The pathway from p-Stat3 to C/EBPδ to myostatin and muscle wasting could identify therapeutic targets that prevent muscle wasting.
在不明机制下，分解代谢状态（如慢性肾脏病（CKD））会导致肌肉质量减少。在 CKD 患者的肌肉活检中，我们发现了激活的 Stat3（p-Stat3），并假设 p-Stat3 引发肌肉消耗。我们创建了肌肉特异性敲除（KO）的小鼠，以防止 Stat3 的激活。在这些小鼠中，CKD 或急性糖尿病模型中体重和肌肉重量的损失受到抑制。抑制 Stat3 激活的小分子产生了类似的反应，表明存在潜在的转化策略。使用 CCAAT/增强子结合蛋白 δ（C/EBPδ）KO 小鼠和 C/EBPδ 敲低或肌肉生长抑制素（一种负性肌肉生长调节剂）敲低的 C2C12 肌管，我们确定 p-Stat3 通过 C/EBPδ 引发肌肉消耗，刺激肌肉生长抑制素。C/EBPδ KO 还改善了 CKD 小鼠的存活率。我们验证了 CKD 患者肌肉中 p-Stat3、C/EBPδ 和肌肉生长抑制素的增加。从 p-Stat3 到 C/EBPδ 到肌肉生长抑制素和肌肉消耗的途径可以确定预防肌肉消耗的治疗靶点。
