NOVEL MECHANISMS MODULATING SKELETAL MUSCLE FUNCTIONS

调节骨骼肌功能的新机制

• 批准号: RGPIN-2020-06481
• 负责人: StPierre, DavidH
• 金额: $ 2.04万
• 依托单位: Université du Québec à Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=741241
• 关键词: NOVEL; MECHANISMS; MODULATING; SKELETAL; MUSCLE

Overall Objective. This research program will elucidate underlying mechanisms by which gut-derived factors and lipid-enriched diets, training and polyphenols (PP) regulate skeletal muscle functions. Justification. This research is prompted by recent findings showing that gut microbiota (GM) and gastrointestinal (GI) peptides influence skeletal muscle mass, contractility and metabolism. Second, high fat (HFD) and Western-type diets (WD) are known to hinder muscle contractility. Thirdly, we recently reported that impaired muscle contractility, lipid metabolism, mitochondrial functions, antioxidant defense and the triggering of inflammation preceded changes in weight gain in young rats fed a HFD. Subsequent transcriptomics and lipidomics analyses have enabled us to identify new genes and lipid moieties that modulate the skeletal muscle. Approach. Collectively, findings have laid the foundation for a NSERC research program that will identify and characterize novel mechanisms by which gut-derived compounds and lipid-enriched diets impact skeletal muscle function and how PPs and exercise may optimize these effects. We are proposing 3 Objectives: (1) Identify new gut regulators of skeletal muscle: This set of experiments that features a library of GI peptides and GM-derivatives in cultured L6 myocytes will provide new insight on how a number of gut-derived factors modulate the skeletal muscle. Thereafter, Wistar rats will be treated with the most bioactive molecules. Absolute force, fatigue resistance and recovery capacity will be measured in muscles. Key pathways regulating muscle mass, fiber typing, metabolism, autophagy, redox state, inflammation and mitochondrial activity will be determined. (2) Define novel lipid mechanisms regulating the gut/skeletal muscle axis: This aim will provide new information on how lipid-enriched diets alter the gut/skeletal muscle axis. Rats will be fed RCD, HFD or WD for 1 to 12 weeks. Dependent variables are identical to Objective 1. Mechanisms by which GI peptides secretion, the production of GM-derived compounds and intestine permeability affect skeletal muscle functions will be elucidated. (3) Design interventions to optimize skeletal muscle functions: These experiments will provide new information on how PP and exercise impact the skeletal muscle. A Library of PPs will be screened in L6 cells (see Objective 1). Rats fed RCD will be supplemented with the most potent form of PP and submitted to endurance, resistance, high intensity interval training or remain sedentary. Dependent variables described in Objectives 1 and 2 will be measured. Significance. This proposed research will have broad implications for NSERC by identifying novel nutritional and physical exercise interventions optimizing muscle functions in a number of apparently unrelated areas such as human and animal health (growth, aging and diseases), sports performance, livestock production and astronauts involved in prolonged space missions.

总体目标。这项研究计划将阐明肠源性因子和富脂饮食、训练和多酚(PP)调节骨骼肌功能的潜在机制。正当性。最近的研究结果表明，肠道微生物区系(GM)和胃肠道(GI)多肽影响骨骼肌质量、收缩能力和新陈代谢，从而推动了这项研究。其次，众所周知，高脂肪(HFD)和西式饮食(WD)会阻碍肌肉收缩。第三，我们最近报道，在喂食高脂饲料的幼鼠体重增加之前，肌肉收缩、脂肪代谢、线粒体功能、抗氧化防御和引发炎症的损害先于体重增加。随后的转录学和脂质组学分析使我们能够识别调节骨骼肌的新基因和脂质部分。接近。总而言之，这些发现为NSERC的一项研究计划奠定了基础，该计划将确定和描述肠道衍生化合物和富含脂肪的饮食影响骨骼肌功能的新机制，以及PPS和运动如何优化这些影响。我们提出了三个目标：(1)确定新的骨骼肌肠道调节因子：这组实验以培养的L6肌细胞中的GI多肽和GM-衍生物库为特色，将为一些肠源性因子如何调节骨骼肌提供新的见解。此后，Wistar大鼠将接受最具生物活性的分子治疗。绝对力、耐疲劳性和恢复能力将以肌肉为单位进行测量。将确定调节肌肉质量、纤维类型、新陈代谢、自噬、氧化还原状态、炎症和线粒体活动的关键途径。(2)确定调节肠道/骨骼肌轴的新的脂质机制：这一目标将为富脂饮食如何改变肠道/骨骼肌轴提供新的信息。分别给予RCD、HFD或WD喂养1~12周。因变量与目标1相同。GI多肽分泌、GM衍生化合物的产生和肠道通透性影响骨骼肌功能的机制将被阐明。(3)设计干预措施以优化骨骼肌功能：这些实验将提供有关PP和运动如何影响骨骼肌的新信息。将在L6细胞中筛选PPS库(见目标1)。喂食RCD的大鼠将补充最有效的PP形式，并接受耐力、抵抗、高强度间歇训练或保持久坐不动。将衡量目标1和目标2中描述的因变量。意义重大。这项拟议的研究将通过确定新的营养和体育锻炼干预措施，优化一些明显无关的领域的肌肉功能，如人类和动物健康(生长、衰老和疾病)、运动表现、牲畜生产和参与长期太空任务的宇航员，从而对NSERC产生广泛影响。