Thèse Métabolisme des Acides Gras dans les Cellules Souches Musculaires H/F - Doctorat.Gouv.Fr

Établissement : Université Grenoble Alpes École doctorale : CSV- Chimie et Sciences du Vivant Laboratoire de recherche : Laboratoire Bioénergétique Fondamentale et Appliquée Direction de la thèse : Uwe SCHLATTNER ORCID 0000000311595911 Début de la thèse : 2026-10-01 Date limite de candidature : 2026-06-30T23:59:59 La capacité de régénération du muscle squelettique après une lésion est assurée par les cellules souches musculaires (MuSCs). Dans diverses conditions pathologiques, la fonction des MuSCs est altérée, ce qui réduit leur capacité de régénération et contribue ainsi à la dysfonction musculaire. Les mécanismes sous-jacents à ces altérations restent toutefois mal compris. Des études récentes suggèrent que les changements métaboliques jouent un rôle clé dans la régulation de la fonction des MuSCs. Par conséquent, cibler le métabolisme de ces cellules représente une opportunité prometteuse pour moduler leur fonction à des fins thérapeutiques.
Parmi les différentes voies métaboliques, le métabolisme des acides gras est central, intervenant dans la production d'ATP, le stockage de l'énergie et la synthèse des membranes. Cependant, peu d'études sur les cellules souches ont exploré le rôle des lipides, se concentrant surtout sur l'oxydation des acides gras. Bien que ces recherches soulignent l'importance du métabolisme des acides gras dans les MuSCs, elles ne décrivent pas encore en détail les mécanismes moléculaires impliqués.
Nous proposons que le programme myogénique nécessite une adaptation spécifique du pool d'acides gras pour soutenir la dynamique des membranes, le métabolisme et la signalisation cellulaire. Le projet vise à : 1) identifier les acides gras essentiels à un programme myogénique optimal ; 2) décrypter leurs mécanismes d'action en examinant leurs effets sur le métabolisme énergétique et la régulation épigénétique ; 3) développer des stratégies pour moduler le métabolisme des acides gras en ciblant leur synthèse ou leur disponibilité, afin de promouvoir la quiescence, la prolifération ou la différenciation des MuSCs.
Nous anticipons que ce projet apportera des avancées significatives dans la compréhension de la régénération musculaire et ouvrira la voie à de nouvelles approches thérapeutiques.
Skeletal muscle exhibits remarkable plasticity, capable of adapting its mass in response to locomotor demand, as well as regenerating after multiple injuries. These adaptive and regenerative abilities are driven by muscle stem cells (MuSCs), commonly known as satellite cells. While typically quiescent, MuSCs become activated to support muscle hypertrophy or repair following injury (Relaix et al. 2021). Maintaining a functional MuSC pool is critical for long-term muscle homeostasis. Over recent decades, impaired MuSC function and reduced muscle regenerative capacity have been identified in various pathological conditions, significantly contributing to muscle dysfunction. However, the underlying mechanisms leading to MuSC exhaustion remain poorly understood, and an in-depth characterization of the factors that regulate MuSC states is essential for the development of new therapeutic strategies. MuSCs are also the most effective cell type for muscle cell therapy, with numerous studies demonstrating improved muscle function following MuSC transplantation (Montarras et al. 2005). Despite this potential, a significant limitation challenges its use for both mechanistic research and cell-based therapeutic applications. Indeed, current MuSC culture conditions are not fully adequate, as ex vivo expansion diminishes their regenerative capacity mainly due to premature differentiation (Montarras et al. 2005).
Recent studies across various tissues suggest that adult stem cell fate is regulated by changes in metabolic pathways, where shifts in substrate preference may trigger genetic reprogramming via secondary metabolite production (Folmes et al. 2012). As a result, modulation of metabolic pathways significantly impacts stem cell function and may have important pathological consequences. Targeting stem cell metabolism therefore represents an innovative opportunity to control cell fate for therapeutic purposes (Relaix et al. 2021). Among the various metabolic pathways, we focus on fatty acid (FA) metabolism because it sits at the crossroad of multiple essential cellular processes. FA metabolism not only fuels ATP production through mitochondrial oxidation and contributes to energy storage, but also governs membrane dynamics via phospholipid synthesis and regulates intracellular signaling. Moreover, recent discoveries have revealed that intermediates of FA metabolism regulate histone acetylation and acylation, providing a direct molecular link between metabolic state, epigenetic remodeling, and cell fate decisions (Jo et al. 2020; McDonnell et al. 2016). Disruption of FA metabolism can have severe effects on muscle homeostasis. On one hand, impaired fatty acid oxidation (FAO), as seen in very-long chain acyl-CoA dehydrogenase deficiency, leads to muscle dysfunction, including episodes of rhabdomyolysis (Olpin 2013). On the other hand, defective synthesis of very long chain fatty acids (VLCFA) due to 3-Hydroxyacyl-CoA Dehydratase 1 (Hacd1) deficiency results in congenital myopathy with fiber-type disproportion (Muhammad et al. 2013), impaired muscle metabolism and myoblast fusion (our results (Prola et al. 2021; Blondelle et al. 2015)). Additionally, excessive dietary FA intake contributes to muscle mass loss (Li et al. 2022). In the stem cell field, few studies have explored the role of lipids, and most of them focused solely on FA oxidation (FAO). Yet, they have demonstrated that reducing FA uptake, oxidation or storage in lipid droplets impairs MuSC function (Yue et al. 2022, 2025; Wang et al. 2024). While these findings underscore the importance of FA metabolism in MuSCs function, they lack a detailed molecular description of the mechanisms involved. Building on these promising insights, our work aims to uncover this largely unexplored aspect of FA metabolism in MuSCs. We hypothesize that a deeper investigation of FA roles will reveal novel regulatory mechanisms and open new therapeutic avenues.
Published studies and our preliminary data have established that fatty acids (FA) metabolism plays a crucial role in MuSC function. However, the molecular mechanisms involved remain unknown. This research program aims to first identify which FAs are essential for an efficient myogenic program. Next, we will unravel their impact on energy metabolism and epigenetics. Finally, based on the identified FAs, we will develop strategies to modulate FA metabolism by targeting FA synthesis or availability, in order to specifically promote MuSC quiescence, proliferation or differentiation. Isolation and characterization of muscle stem cells from transgenic mouse models using flow cytometry (FACS). Induction of skeletal muscle injury in mice by intramuscular barium chloride injection, followed by analysis of muscle regeneration processes. Histological and immunofluorescence analyses on muscle sections combined with advanced microscopy imaging. The project will also involve primary cell culture, lipidomic data analysis, and the use of standard molecular and cellular biology techniques, including qPCR, western blotting, gene expression analysis, and protein characterization. The candidate will gain interdisciplinary training at the interface between stem cell biology, metabolism, and muscle physiology.

Les candidats doivent être titulaires d'un Master apportant des connaissances théoriques en biologie cellulaire musculaire ou en physiologie. Un intérêt pour les études utilisant des modèles animaux est requis. Une expérience préalable en biochimie, biologie moléculaire, analyses omiques, ainsi qu'une initiation à l'expérimentation chez le rongeur constitueraient un atout.
Niveau d'anglais requis : intermédiaire supérieur. Le candidat doit être capable d'utiliser la langue efficacement et de s'exprimer avec précision. La maîtrise du français n'est pas obligatoire.