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

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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.