Les mécanismes liant la dynamique mitochondriale à l'état de quiescence et à l'activation des cellules souches musculaires

成体干细胞对于正常组织生理学和压力条件下（如损伤或晚期衰老）是必需的。调节它们的休眠（或静止）状态对于成体干细胞如何维持、激活以及它们的再生潜力是重要的。然而，这种调节是如何发生的和潜在的细胞机制还没有完全理解。我们的初步工作已经发现，线粒体，主要细胞器之一的形状的生理和短暂的变化，调节成体肌肉干细胞（MuSC）的静止状态。我们观察到，干细胞中的线粒体在对环境激活刺激的反应中迅速碎裂。这推动细胞从深度静止中退出，并依赖于称为mTOR的主要细胞复合物。此外，我们发现，在退出休眠后，成年MuSC在组蛋白蛋白复合物中进行修饰（表观遗传变化），这导致基因在细胞中表达方式的变化。在本研究中，我们的目标是深入研究（1）mTOR复合物及其控制的细胞过程在成年MuSC退出深度静止中的作用。(2)线粒体断裂和成年MuSC从休眠状态中退出后发生了什么表观遗传变化，以及这些变化与后续干细胞激活之间的因果关系。为了解决这些问题，我们组建了一个由三个实验室组成的合作团队，每个实验室都拥有独特和互补的专业知识：Laura Hulea博士（mTOR复合物及其控制的细胞过程），Mireille Khacho博士（干细胞生物学和线粒体动力学）和Frédérick Mallette博士（表观遗传调控和衰老）。每个实验室都拥有组织培养和使用小鼠的专门知识和具体工具，以解决上述问题。

Adult stem cells are necessary for normal tissue physiology and under conditions of stress, such as injury or advanced aging. Regulation of their state of dormancy (or quiescence) is important towards how adult stem cells are maintained, activated, as well as their regeneration potential. Yet, how this regulation takes places and the underlying cellular mechanisms are not fully understood.Our preliminary work has uncovered that physiological and transient changes in the shape of mitochondria, one of the major cellular organelles, regulate the quiescent state of adult muscle stem cells (MuSC). We observed that mitochondria in stem cells rapidly fragment in response to an environmental activation stimulus. This pushes the cells toward an exit from deep quiescence and is dependent on a major cellular complex called mTOR. Moreover, we have found that, following exit from dormancy, adult MuSC undergo modifications in histone protein complexes (epigenetic changes), which lead to changes in the way genes are expressed in the cells. This in turn could lead to physiological changes at the cellular and tissue level.In this proposal, we aim to investigate in depth(1) the role of mTOR complexes and the cellular processes they control in the exit from deep quiescence of adult MuSC.(2) what epigenetic changes occur following mitochondria fragmentation and the exit from dormancy of adult MuSC, and what is the causal role between these changes and the subsequence stem cell activation.To tackle these questions, we have formed a collaborative team of three laboratories, each with unique and complementary expertise: Dr Laura Hulea (mTOR complexes and the cellular processes they control), Dr Mireille Khacho (stem cells biology and mitochondria dynamics) and Dr Frédérick Mallette (epigenetic regulation and aging). Each laboratory has the know-how and the specific tools, both in tissue culture and using mice, to address the aforementioned interrogations.