sIL-6R/Stat3反式通路通过PDK4抑制糖代谢诱发恶液质骨骼肌降解的实验研究

恶液质是肿瘤及多种疾病常见的并发症，缺乏有效的防治方法。骨骼肌的进行性萎缩是其典型病理特征。炎症诱导的肌细胞代谢重编程目前被认为是肌肉降解的根源，STAT3在此过程中发挥着关键作用。但在恶液质形成过程中，诱发Stat3异常激活的原因，以及Stat3活化引发肌肉降解的机制目前尚不清楚。我们的前期研究发现，IL-6可溶性受体介导的STAT3反式通路活化，可引发细胞的代谢异常和肌肉降解，STAT3的异常激活可通过抑制丙酮酸代谢，降低细胞的能量合成效率，是诱发肌肉降解的根源。为此我们提出，sIL-6R介导的Stat3反式通路活化，通过FOXO1促进PDK4的表达，减少AcCoA的合成和三羧酸循环的效率，导致细胞的能量代谢障碍，从而激活泛素-蛋白酶体和自噬-溶酶体系统，最终诱发肌肉降解。阻断IL-6反式通路或使用PDK4的抑制剂可保护恶液质的肌肉降解。本课题为深入阐明恶液质的发病机理提供实验依据。

Cachexia syndrome represents a complex clinical picture that occurs in the late stage of several chronic inflammatory diseases and cancer. There are no effective therapeutic strategies currently available, and the progressive weight loss and muscle wasting remain significant clinical problems leads to increased morbidity and mortality. Inflammation induced metabolic reprogramming has been considered as the major cause for the development of skeletal muscle atrophy. STAT3, A signaling pathway that bridge between inflammation and metabolic-endocrine dysfunction, its abnormal activation is the one of the important reason for the induction of cachetic muscle wasting, however, the upstream factors that induce aberrant STAT3 activation and the molecular mechanisms of STAT3-induced muscle atrophy in cancer cachexia remain incompletely understood. Our preliminary study suggested that soluble IL-6 receptor mediated IL-6 “trans-signalling” are the major cause for the induction of consistent STAT3 activation in cancer cachexia, the prolonged STAT3 activation could disturb the energy synthesis by inhibiting the pyruvate metabolism, that trigger the skeletal muscle wasting accordingly. Here we propose that IL-6 “trans-signalling”mediated STAT3 activation could influence the enzyme activity of PDK4 in a FOXO1-dependent manner, this result in the decreased AcCoA generation and reduced TCA cycle rates , the reduced energy generation further activate the ubiquitin proteasome system (UPS) and the autophagy lysosome pathway (ALP), that finally caused the muscle atrophy . Blocking the IL-6 “trans-signalling”activation or administration of PDK4 inhibitors could up-regulate the activity of PDH and protects against the development of experimental cachetic muscle wasting. This study will provide an experimental bases for further addressing the pathological mechanism and development of effective therapeutic approach of cachexia.