Murine Double Minute-2 signaling pathway regulates exercise-induced angiogenesis in rodent skeletal muscle

小鼠 Double Minute-2 信号通路调节啮齿动物骨骼肌运动诱导的血管生成

• 批准号: 341258-2011
• 负责人: Birot, Olivier
• 金额: $ 1.75万
• 依托单位: York University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=572212
• 关键词: Murine; Double; Minute; signaling; pathway

Skeletal muscles represent more than 40% of our body weight and participate in very important physiological functions such as body mobility or glucose homeostasis. Blood vessels represent a key element of skeletal muscle function. With a remarkable plasticity, capillaries - our smallest blood vessels - ensure a good match between muscle blood perfusion capacities and the needs of our muscle cells in oxygen and nutrients. Physical exercise is a physiological situation that stimulates the formation of new capillaries in our skeletal muscles. This biological process, named angiogenesis, is tightly regulated by stimulatory and inhibitory molecular factors. We have recently demonstrated that a protein named Murine Double Minute-2 (Mdm2) was an important actor of muscle angiogenesis in response to running exercise. However, the molecular mechanisms through which Mdm2 exert its pro-angiogenic action remain unknown. Our research program will pursue our initial work on Mdm2. We now aim to identify the upstream signaling pathways that regulate Mdm2 activity and expression in response to exercise; and we will also focus on the downstream pathways through which Mdm2 mediates its pro-angiogenic action. Our project will represent an innovative and important contribution in the field of muscle physiology research since we describe here a novel role for Mdm2 in muscle tissue. This will improve our understanding of the cellular and molecular mechanisms that regulate vascular adaptability in skeletal muscle. This might also be of interest in the context of several diseases that affect the muscle vasculature (diabetes, chronic heart failure).

骨骼肌占我们体重的40%以上，并参与非常重要的生理功能，如身体活动或葡萄糖稳态。 血管代表骨骼肌功能的关键要素。毛细血管-我们最小的血管-具有显着的可塑性，确保肌肉血液灌注能力与肌肉细胞对氧气和营养物质的需求之间的良好匹配。体育锻炼是一种生理情况，刺激我们骨骼肌中新毛细血管的形成。这种生物学过程称为血管生成，受到刺激性和抑制性分子因子的严格调控。 我们最近证明了一种名为小鼠双分钟-2（Mdm 2）的蛋白质是响应跑步运动的肌肉血管生成的重要因素。然而，Mdm 2发挥其促血管生成作用的分子机制仍然未知。 我们的研究计划将继续我们对Mdm 2的初步工作。我们现在的目标是确定上游信号通路，调节Mdm 2的活性和表达，在响应运动，我们也将集中在下游途径，通过Mdm 2介导其促血管生成的行动。 我们的项目将代表肌肉生理学研究领域的创新和重要贡献，因为我们在这里描述了Mdm 2在肌肉组织中的新作用。这将提高我们对调节骨骼肌血管适应性的细胞和分子机制的理解。这在影响肌肉脉管系统的几种疾病（糖尿病、慢性心力衰竭）的背景下也可能是感兴趣的。