循环miR-130b调控骨骼肌能量代谢的机制研究

Obesity, which results from energy imbalance in energy metabolism, has become a major public health problem. In our previous study, we discovered that 1) serum levels of miR-130b are positively correlated with obesity; 2) serum miR-130b is a powerful predictor for metabolic syndrome; 3) adipocytes are able to secret miR-130b; 4) muscle cells can uptake extracellular miR-130b; 5) miR-130 is capable of repressing the expression of target gene PGC-1a, a key regulator of energy metabolism. Therefore, we speculated that miR-130b might mediate the regulation of muscle by adipose tissue and abnormally elevated serum miR-130b might play a role in the development of obesity-associated diseases. However, the detailed molecular mechanism involved remains unclear. Here, we apply for a research grant to continue our work to better understand the role of miR-130b in metabolic regulation. We plan to identify more key targets of miR-130b in skeletal muscle, explore their individual roles and their mutual relationship. We also would like to investigate the regulation of miR-130b transportation and test whether miR-130b could serve as a target to improve the metabolism in mice. Together, we hope our study of the role of miR-130b in metabolic regulation will not only help us to understand the effect of miR-130b in the pathogenesis of metabolic disorders but also provide rationale and novel strategies for controlling metabolic diseases.

肥胖已成为严重影响人们身体健康的公共卫生问题，肥胖系机体的能量代谢失衡所致。申请人前期研究发现，肥胖患者血清miR-130b水平显著升高，miR-130b可被脂肪细胞分泌，也可以被骨骼肌细胞吸收。研究还发现，miR-130b能够调节能量代谢的关键基因PGC-1a的表达。由此申请人提出假设，miR-130b介导脂肪对骨骼肌能量代谢的调控，血清miR-130b水平异常可能参与肥胖相关疾病的发生发展。为进一步验证该科学假设，本项目将探讨miR-130b如何调节骨骼肌细胞PGC-1a基因表达，以及下游参与能量代谢调节的靶基因所介导的作用以及相互之间的关系。本项目还将探索循环miR-130b的转运机制，尝试将其作为干预靶点改善小鼠能量代谢的可行性。本课题将通过揭示循环miR-130b调控骨骼肌能量代谢的分子机制，阐明其水平异常在代谢性疾病发生发展过程中的作用，为预防治疗代谢性疾病提供依据和新思路。

项目负责人前期研究发现，肥胖患者血清miR-130b水平显著升高，miR-130b可被脂肪细胞分泌，也可以被骨骼肌细胞吸收。研究还发现，miR-130b能够调节能量代谢的关键基因PGC-1a的表达。由此申请人提出假设，miR-130b介导脂肪对骨骼肌能量代谢的调控，血清miR-130b水平异常可能影响骨骼肌相关疾病的发生发展。在本项目的研究中，我们较为全面的分析了miR-130b在骨骼肌中的生物学功能。我们研究发现，miR-130b可以抑制成肌细胞的增殖，促进成肌细胞的分化。我们还发现，Sp1是miR-130b的直接靶基因，Sp1可能介导了miR-130b对肌肉生成的调控作用。与此发现一致的是，我们发现miR-130b的表达水平和Sp的mRNA水平在体外骨骼肌细胞肌肉生成过程中成负相关，在不同代谢类型的肌肉中也成负相关。和miR-130b抑制慢肌中脂肪酸氧化关键基因PGC1-a表达的作用一致，我们发现miR-130b的水平在快肌中较高，在慢肌中较低。此外，我们研究发现，提高miR-130b的水平可以通过增强成肌改善成肌分化过程加速受损肌肉的恢复，提示miR-130b可以作为治疗靶点来防治相关的骨骼肌疾病。最后，我们还分析了miR-130b在临床骨骼肌样本中的表达，发现miR-130b在肌营养不良患者的骨骼肌中水平降低，进一步提示miR-130b在骨骼肌再生和相关骨骼肌疾病发展过程中起作用。有关脂肪组织与骨骼肌的相互作用，特别是脂肪组织来源的miR-130b对骨骼肌代谢和相关疾病的影响的研究还在继续当中。综上所述，我们的研究发现miR-130b/Sp1轴在成肌细胞增殖、分化、骨骼肌代谢和再生过程中起调控作用。我们的研究不但临床相关性强，而且为骨骼肌损伤和严重的骨骼肌疾病患者的治疗提供了新的治疗策略。

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