Les cellules souches musculaires, ou cellules satellites, adoptent différents états en transitant de quiescence à prolifération et différentiation. Ces transitions s'accompagnent de variations des demandes énergétiques. Il demeure cependant incertain comment la modulation du métabolisme énergétique peut dicter la spécification d'un état cellulaire donné. Mon projet de thèse a eu pour objectif principal la caractérisation des voies du métabolisme énergétique à l’œuvre dans les différents états cellulaires, et comment leur modulation peut influencer ces états. Nous montrons ainsi que les cellules satellites quiescentes ont de faibles besoins énergétiques et que la phosphorylation oxydative est altérée au cours du vieillissement ainsi que dans les cellules survivant après la mort de l'animal. Au cours de la formation du tissu en croissance ou en régénération chez l'adulte, nos résultats indiquent de larges différences dans leurs demandes énergétiques. Les cellules fœtales ont une faible demande respiratoire et reposent essentiellement sur la glycolyse par rapport aux cellules adultes en cours de régénération. L'altération de la b-oxidation peroxisomale et non mitochondriale induit une différentiation précoce des cellules satellites. L'inhibition pharmacologique des b-oxidations peroxisomale et mitochondriale après blessure aiguë montre différentes contributions de ces organelles à la régénération musculaire. Les transitions entre différents états des cellules satellites s'accompagnent de modifications drastiques de leurs besoins énergétiques et l'altération de vois métaboliques spécifiques peut altérer le destin des cellules myogéniques et la régénération musculaire. / Muscle stem (satellite, MuSC) cells acquire different cell states as they need to pass from quiescence to proliferation and differentiation to support muscle homeostasis. Some of these changes are accompanied by changes in energy demands. However, it is currently unclear whether modulation in the energy metabolism pathways can in turn influence the commitment to a specific cell state. A central focus of my thesis project is to characterise the energy metabolism pathways that act in the different phases of lineage progression and how their modulation can influence the state of the cell. We show that quiescent cells have low energetic demands and OxPhos is perturbed during aging, as well as in cells that survive after death. We also compared different proliferative states, both during muscle growth and regeneration, and our results indicate a surprising difference in their metabolic requirements. Gene expression profiling and bioenergetics analysis showed that foetal cells have a low respiration demand and rely mostly on glycolysis when compared to regenerating MuSCs. Furthermore, we show distinct requirements for peroxisomal and mitochondrial mediated fatty acid oxidation (FAO) in myogenic cells. Altering peroxisomal but not mitochondrial FAO promotes early differentiation of satellite cells. Experiments using acute muscle injury and pharmacological block show differential requirements for these organelles during regeneration. These observations indicate that changes in the cell state of muscle stem cells lead to significant changes in metabolic requirements and altering specific metabolic pathways can have an impact on myogenic cell fate and the regeneration process.

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Nel presente lavoro vengono suggerite nuove strategie di lettura per un’opera che costituisce un unicum, non solo nella produzione narrativa di Italo Calvino, ma certamente anche nella storia letteraria del Novecento. Il castello dei destini incrociati (1973) viene interpretato in senso cartografico, come il tentativo di mappare un mondo labirintico, dai significati inesauribili e comunque destinato a farsi inghiottire dal gorgo della modernità. Pur conservando i tratti del romanzo enciclopedico, viene messo in luce come il Castello si sottragga al desiderio di rappresentare la totalità, scegliendo piuttosto la strada del potenziale e della metamorfosi, nel tentativo di individuare i fattori primi di ogni storia narrabile. Un po’ torre di Babele e un po’ arca dell’alleanza, emerge nel lavoro come il libro nasca dal bisogno di verificare le ragioni della letteratura e di rivisitare il ruolo dell’intellettuale: sul finire degli anni sessanta, Calvino allestisce in chiave allegorica e figurale un’allarmata riflessione sulla convivenza, profetizzando l’apocalisse di un mondo che è chiamato a recuperare l’antica fiducia nella progettazione e nell’utopia. / This work suggests new reading strategies for a novel that represents a singular event, not only in Italo Calvino’s narrative production, but also in the history of Nineteenth-Century literature. The Castle of Crossed Destinies (1973) is approached in a cartographical way, as an attempt to give the map of a labyrinthine world, complicated by inexhaustible meanings and, in any case, destined to be swallowed by Modernity’s wheel. Though conserving the features of the encyclopaedic novel, the Castle is shown as a book that tries to dodge the desire to represent the world as a whole, as a totality: on the contrary, it chooses to go through the paths of potentiality and metamorphosis, seeking the prime factors of every possible story. The Castle is a sort of Tower of Babel, an Ark of the Covenant: Savio’s thesis underlines that this novel grows out of the need to check the reasons of literature and to rethink the role of intellectuals: in the end of the Sixties, allegorically and figurally, Calvino sets up an alarmed reflection about the coexistence of mankind, foretelling the apocalypse of a world that is called to rescue its old faith in planning and utopia.