Triggering human myoblast differentiation: from EGFR to myogenic transcription factors
Prof. Laurent Bernheim, Dr Maud Frieden, Dr Stéphane König. Department of Fundamental Neurosciences, University Medical Center, Geneva
Abstract (Lay summary see below)
The major goal of our laboratory is to decipher the cellular and molecular mechanisms that control the transition from proliferation to differentiation of human primary myoblasts with the long-term goal of improving the survival of myoblasts injected for the treatment of muscle disorders.
In previous works, we showed that initiation of human myoblast differentiation requires a negative shift (hyperpolarization) of the resting potential of myoblasts that depends on the activation of Kir2.1 potassium channels. These channels are activated by a tyrosine dephosphorylation. Recently, we discovered that Epidermal Growth Factor Receptor (EGFR) activity is down regulated during the first hour of differentiation, and that this downregulation triggers Kir2.1 channels activity.
In parallel studies, we also showed that the Kir2.1-linked hyperpolarization produces a Ca2+ entry through store-operated Ca2+ channels. This Ca2+ entry is able to activate at least two Ca2+-dependent signaling molecules, calcineurin and CaMK, that eventually lead to the expression of myogenic transcription factors and muscle specific proteins (Myogenin, MEF2, MyHC).
The two aims of the present proposal are to decipher:
1. the molecular mechanisms linking EGFR activity and Kir2.1 channel inactivation;
2. how Ca2+-dependent pathways (specifically, calcineurin and CaMK) induce the expression and activation of myogenin and MEF2 at the onset of differentiation?
Lay summary
La régénération du muscle squelettique humain se fait par différenciation et fusion des myoblastes
La fibre musculaire squelettique est une grande cellule qui possède de nombreux noyaux. Elle est issue de la fusion de petites cellules pourvues d’un seul noyau, les myoblastes. Tous les myoblastes ne fusionnent cependant pas. Des myoblastes dormants, appelés cellules satellites, sont observés sur les fibres musculaires adultes. Les cellules satellites sont activées en cas de traumatismes musculaires, par exemple lors d’étirements musculaires excessifs. Lorsqu’elles sont activées, les cellules satellites donnent naissance à des myoblastes qui se multiplient et fusionnent entre eux pour former de nouvelles fibres musculaires.
Un intérêt particulier pour les cellules satellites vient de leur utilisation potentielle à des fins thérapeutiques. Face à l’atrophie musculaire induite par les myopathies, la cellule satellite ou sa cellule fille, le myoblaste, pourrait être utilisée comme matériel de greffe. Convaincu qu’une utilisation efficace des cellules satellites dépendra d’une bonne connaissance des mécanismes moléculaires leur permettant de se différencier et de fusionner en fibres musculaires, notre travail consiste à étudier les myoblastes humains en culture durant leur maturation et leur fusion.
Notre groupe a montré que la différenciation des myoblastes, première étape menant à la formation des myotubes, dépend de variations du calcium cytosolique générées grâce à un influx calcique appelé SOCE (Store Operated Calcium Entry). Cet influx permet in fine l’expression de facteurs de transcription nucléaires spécifiques de la différenciation musculaire. Nous avons aussi montré que le récepteur à l’EGF (Epidermal Growth Factor) est un régulateur incontournable de la différenciation des myoblastes humains. L’activité de ce récepteur est inhibée au tout début du processus de différenciation et cette inhibition, à travers une cascade moléculaire encore inconnue, aboutit à une amplification drastique (et nécessaire à la différenciation des myoblastes) du SOCE. Le but de notre recherche actuelle est d’identifier les maillons manquants entre l’inhibition du récepteur à l’EGF et l’amplification du SOCE.
Progetti
- Nuovi progetti di ricerca dal 2024
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