耐力训练改善散发性包涵体肌炎患者骨骼肌有氧代谢能力的机制研究

Sporadic inclusion body myositis (sIBM), a sporadic inflammatory muscle disease, may related to inflammatory response and degeneration of muscle fibers. Cases of sIBM have poor response to the conventional therapy of immune suppression and immune regulation, which at most could stabilize or improve the condition of the patients with sIBM temporarily. Recent studies showed that endurance training can improve the aerobic capacity and muscle strength of skeletal muscle and the life qualities of sIBM patients. However, the molecular mechanism is still not clear. This study is a cohort investigation which include sIBM patients accepting endurance training (12 weeks of aerobic training combined with muscle strength training). The effect of endurance training, including cycling time, VO2max and muscle strength, would be determined. The differential expression of microRNA, mRNA and proteins in muscle biopsy specimens before and after the 12-week training would be investigated by the microarray, quantitative proteomics and immunohistochemical techniques. Moreover, these results would be comprehensively analyzed through the DAVID database, Gene Ontology and KEGG biological system to identify key genes associated with signaling pathways of aerobic metabolism and explore molecular mechanisms involved in the improvement of aerobic metabolism by endurance training, which would indicate the initiating factors of inclusion body myositis and provide a new target for new drug development.

散发性包涵体肌炎是一种散发性炎性肌病，其发病可能与免疫炎性反应和肌纤维变性有关，对传统免疫抑制或免疫调节治疗反应较差。近期的研究显示耐力训练可提高sIBM患者骨骼肌的有氧代谢能力，肌肉力量和患者的生活质量。然而其分子机制尚不明确。本课题拟纳入sIBM患者进行队列研究，以耐力训练（12周有氧训练联合肌肉力量训练）为干预措施，观察耐力训练对患者骨骼肌有氧代谢能力（踏车耐力时间，最大摄氧量）及疾病活动度等方面的影响，应用基因芯片、定量蛋白组学及免疫组化等技术对干预前后肌肉活检标本进行microRNA、mRNA及蛋白的差异表达分析，并通过DAVID数据库、Gene Ontology及KEGG等生物学系统综合分析，鉴定出耐力训练改善sIBM患者骨骼肌有氧代谢能力的相关信号通路及处于核心地位的关键基因，明确耐力训练改善骨骼肌有氧代谢能力的分子机制，以期明确疾病的始动因素，为靶向药物的研发提供新的靶点。

散发性包涵体肌炎（sIBM）是一种炎性肌病，发病的分子机制尚不明确。本课题收集sIBM、多肌炎、皮肌炎、免疫坏死性肌病患者的临床及肌肉病理资料，分析其临床及病理特点；采用二代测序及蛋白组学技术对不同组别的肌肉活检标本进行全转录组及蛋白差异表达鉴定，并通过Gene Ontology及KEGG等行综合生物信息学分析。.结果显示：1）sIBM首发症状多为双下肢无力；肌电图为肌源性损害，病理特点为肌纤维萎缩呈小角形和小圆形、镶边空泡及单核细胞浸润。2）与正常对照组相比，sIBM组共检测到491个差异表达mRNA，其中326个上调，165个下调。GO及KEGG分析显示差异基因富集的生物学过程为：T细胞增殖、黏附、聚集、活化、抗原加工及提呈；氧化应激反应、活性氧物质代谢、血管生成调节、细胞凋亡及能量代谢等。富集的信号通路包括TCR、JAK-STAT、TLR、TNF、MAPK、HIF-1及FoxO等。涉及的主要基因包括：PIK3CG、ZAP70、CD8A、CD74；IL12B、CISH、SOCS3等。sIBM组共检测到116个差异表达的miRNA，其中30个上调，86个下调，差异表达miRNA靶基因富集的生物学过程主要包括：突触信号，突触可塑性调节、神经发育等，相关miRNA包括miR-423-5p、miR-29c-3p等。3）蛋白组学：与正常对照组相比，sIBM组鉴定出101种差异蛋白质，其中54个上调、47个下调，参与的生物学功能包括肌肉收缩、氧化应激反应等；共参与19条信号通路，如紧密连接、肌肉收缩等。.综上，上述基因及蛋白表达的变化导致sIBM肌肉多种生物学过程异常，包括免疫反应活化、抗氧化反应能力下降；肌细胞增殖受抑，能量代谢紊乱。受影响的信号通路包括TCR、JAK-STAT、TLR、TNF等。这些病理生理因素与sIBM发病密切相关，为探索sIBM的新治疗策略奠定了一定的基础。.