骨骼肌分泌因子Musclin对全身糖脂代谢稳态的调控作用和机制研究

Diabetes has become a global epidemic that severely affects human health. Skeletal muscle metabolic dysregulation is the primary defect in the development of type 2 diabetes and is often associated with a shift from oxidative to glycolytic metabolism. However, whether this metabolic switch is detrimental or adaptive for metabolic homeostasis remains uncertain. We recently identified BAF60c, a subunit of the SWI/SNF chromatin-remodeling complex, as a core component of a regulatory cascade that drives glycolytic myofiber metabolism. Interestingly, muscle specific transgenic expression of BAF60c protects mice from diet-induced glucose intolerance and hepatic steatosis. Mechanistically, BAF60c promotes muscle glycolytic metabolism and glucose utilization through Deptor-mediated AKT activation. In addition, our preliminary studies also found that BAF60c significantly suppressed the expression of Musclin, a muscle-enriched secreted factor. Remarkably, adenoviral-mediated overexpression of Musclin resulted in elevated blood glucose level in mice and upregulation of hepatic genes involved in gluconeogenesis and lipid synthesis. Based on these data, we hypothesize that Musclin-mediated inter-organ crosstalk may play a critical role in the control of whole body metabolic homeostasis by muscle BAF60c. In this proposal, using a combination of transgenic mouse models, adenoviral-mediated gene expression, CRISPR-Cas9-based genome editing, and various metabolism-analyzing approaches, we plan to elucidate the role of Musclin in the control of whole body energy homeostasis, and the significance and mechanism of Musclin in metabolic control by muscle BAF60c. Successful completion of this study will provide new insights into the mechanism of inter-organ crosstalk in metabolic control, and form the basis for the development of new therapeutic interventions for diabetes and its associated complications.

2型糖尿病伴随着骨骼肌红肌向白肌代谢功能的转变，但二者的因果关系尚不清楚。我们近期研究发现了一条以染色质重塑因子BAF60c为核心分子的调控白肌代谢功能的关键信号通路。骨骼肌特异性BAF60c转基因小鼠能够预防由肥胖引起的高血糖和脂肪肝。BAF60c通过Deptor/AKT信号通路促进骨骼肌本身对葡萄糖的利用。同时，BAF60c显著抑制骨骼肌分泌因子Musclin的表达。而Musclin过表达能够引起小鼠高血糖和肝脏中糖异生和脂肪合成相关基因表达上调。这些结果暗示骨骼肌BAF60c还可能通过Musclin介导的组织间对话影响全身糖脂代谢。本项目将利用BAF60c转基因和敲除小鼠、腺病毒介导的基因过表达和CRISPR-Cas9介导的Musclin基因敲除技术，从动物、细胞和分子三个水平，深入研究Musclin对全身糖脂代谢的调控作用，及其在骨骼肌BAF60c对全身代谢稳态调控中的意义和机制。

糖尿病日益成为严重危害人类健康的重大疾病。2型糖尿病伴随者骨骼肌红肌向白肌代谢功能的转变。我们近期研究发现了一条以染色质重塑因子BAF60c为核心分子的控制白肌代谢的关键信号通路。骨骼肌特异性BAF60c转基因小鼠能够预防由肥胖引起的高血糖和脂肪肝。BAF60c通过Deptor/AKT信号通路促进骨骼肌本身对葡萄糖的利用。同时，BAF60c显著抑制骨骼肌分泌因子Musclin的表达，提示骨骼肌BAF60c还可能通过Musclin介导的组织间对话影响全身糖脂代谢。本项目利用BAF60c和Musclin骨骼肌特异性转基因和基因敲除小鼠模型，AAV介导的Musclin过表达和CRISPR-Cas9介导的基因敲除技术，利用基因组学、转录组学以及多种细胞生物学技术，在动物、细胞和分子三个水平，我门发现骨骼肌分泌因子Musclin直接结合和调控肝脏和脂肪组织的能量代谢，进而在全身糖脂代谢稳态调控中发挥重要作用。进一步研究发现骨骼肌中BAF60c通过表观遗传学机制调控Musclin的基因表达和分泌，进而影响靶组织以及全身的糖脂代谢稳态。更重要的是，我们发现肥胖和糖尿病人和小鼠血液中Musclin的水平显著升高，而用中和抗体抑制Musclin的活性能够显著改善高脂饮食诱导的小鼠肥胖和2型糖尿病。本研究揭示了骨骼肌分泌因子Musclin介导的骨骼肌和其它代谢组织之间的对话在2型糖尿病的发病过程中发挥重要作用。提示血液中Musclin的水平可以作为评价代谢综合征严重程度的重要诊断指标，而Musclin中和抗体有望进一步开发成为新型代谢综合征治疗药物,为代谢性疾病患者带来新的曙光。