NOVEL MECHANISMS MODULATING SKELETAL MUSCLE FUNCTIONS

总体目标。这项研究计划将阐明肠道衍生因子和富含脂质的饮食，训练和多酚（PP）调节骨骼肌功能的潜在机制。理由。这项研究是由最近的研究结果表明，肠道微生物群（GM）和胃肠道（GI）肽影响骨骼肌质量，收缩力和代谢。其次，高脂肪（HFD）和西式饮食（WD）是已知的阻碍肌肉收缩。第三，我们最近报道，受损的肌肉收缩力，脂质代谢，线粒体功能，抗氧化防御和炎症的触发之前的变化，在年轻大鼠喂HFD体重增加。随后的转录组学和脂质组学分析使我们能够确定新的基因和脂质部分，调节骨骼肌。 Approach.总的来说，研究结果为NSERC研究计划奠定了基础，该计划将确定和表征肠道衍生化合物和富含脂质的饮食影响骨骼肌功能的新机制，以及PP和运动如何优化这些效果。 我们提出了3个目标：（1）确定新的骨骼肌肠道调节因子：这组实验的特点是在培养的L 6肌细胞中的GI肽和GM衍生物的库将提供新的见解如何肠道衍生因子调节骨骼肌。此后，将用最具生物活性的分子治疗Wistar大鼠。绝对力量、抗疲劳性和恢复能力将在肌肉中测量。将确定调节肌肉质量、纤维分型、代谢、自噬、氧化还原状态、炎症和线粒体活性的关键途径。 (2)定义调节肠道/骨骼肌轴的新脂质机制：这一目标将提供有关富含脂质的饮食如何改变肠道/骨骼肌轴的新信息。大鼠将喂食RCD、HFD或WD 1至12周。因变量与目标1相同。将阐明GI肽分泌、GM衍生化合物的产生和肠通透性影响骨骼肌功能的机制。 (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L 6细胞中筛选PP文库（见目标1）。喂食RCD的大鼠将补充最有效形式的PP，并进行耐力、阻力、高强度间歇训练或保持久坐不动。将测量目标1和2中描述的因变量。意义这项拟议的研究将对NSERC产生广泛的影响，通过确定新的营养和体育锻炼干预措施，优化一些明显不相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。

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.