Reference : UMR8104-FLOBRI-001
Workplace : PARIS 14
Date of publication : Saturday, May 14, 2022
Scientific Responsible name : Florian Britto et Thierry Launay
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 1 October 2022
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly
Description of the thesis topic
Many chronic pathological conditions (Obesity, physical inactivity, COPD, diabetes, cancer cachexia, immobilization, treatment with glucocorticoids, sarcopenia, etc.) cause muscle deconditioning resulting in impaired muscle function, loss of autonomy, reduction in quality of life, as well as an increase in hospitalizations and patient mortality. Identifying the mechanisms involved in muscle deconditioning is therefore a very important socio-economic objective. The development of therapeutic strategies to preserve the muscle function of patients is also a major challenge in the treatment of these pathologies.
Interestingly, muscle deconditioning specifically affects the fastest fibers (type IIx in humans and IIb in rodents) under these pathophysiological conditions. Indeed, type IIx fibers will be the first to atrophy or die in the most serious cases such as peripheral neuropathies. The first objective of this project is to identify the mechanisms responsible for the specific impairment of fast fibers during muscle deconditioning. Physical activity is currently the only effective treatment to prevent (slow down) muscle deconditioning. However, the pathological conditions mentioned above cause resistance to anabolism (reduction of the effects of exercise or nutritional supplements). The second objective of this study is to identify the mechanisms responsible for the protective effects of physical activity on muscle deconditioning and the resistance to anabolism observed in patients.Scientific objectives/hypotheses/issues.
The project aims to highlight the cellular mechanisms involved in muscle deconditioning (including resistance to anabolism) and the protective mechanisms induced by physical activity. Based on the literature and our preliminary results we hypothesize that: i) fast fibers are genetically more sensitive to atrophy and resistant to hypertrophy, ii) than sedentary lifestyle (associated with chronic pathologies) which is known to inducing the fast phenotype is an aggravating factor in muscle deconditioning, iii) conversely, endurance training would protect the muscle from deconditioning by converting fast fibers into slower fibers thereby bypassing atrophic or energy resistance genetic programs hypertrophy.In order to verify our hypotheses, we will subject sedentary or active wild mice (voluntary activity on a wheel) to muscle deconditioning induced by treatment with Dexamethasone or a resistance training protocol (activity wheel with increasing resistance). To prove that our results are indeed linked to the typology of the fibers, we have in the laboratory a conditional murine mutant for the transcription factor responsible for the expression of the rapid phenotype SIX1. We have shown that the deletion of Six1 leads to a slow phenotype which, according to our hypothesis, would confer on Six1-/- mice a resistance to muscle deconditioning even in sedentary conditions as well as a better response to hypertrophy. We then propose to describe in more detail the molecular mechanisms that can explain these differences in responses between the types of fibres.
The literature and the preliminary results that we have obtained allow us in particular to hypothesize that the proteins, REDD1, REDD2, Deptor, Myostatin and AMPK could be involved in the processes of specific atrophy of type IIx/IIb fibers as well as than in their resistance to anabolism. In particular, we will test the involvement of REDD1 in the specific atrophy of fast fibers during muscle atrophy induced by glucocorticoids in sedentary Redd1-/- mice (inducible specific muscle knockouts present in laboratories).
This thesis will take place at the Institut Cochin UMR8104 CNRS/Université de Paris Cité/INSERM (U1016) and will be funded as part of the GDR-Sport project. The Cochin Institute is located in the heart of Paris (14th arrondissement) and brings together many research teams working on a wide variety of subjects. The thesis will take place in the Neuromuscular Development, Genetics and Physiopathology team (directed by Pascal Maire and Athanassia Sotiropoulos) under the supervision of Florian Britto (MCU STAPS) and Thierry Launay (MCU STAPS). The team's work focuses on identifying the cellular mechanisms involved in muscle plasticity under pathological and physiological conditions.
Profile and skills required:
- Master's degree at the date of recruitment (01/10/2022)
-Knowledge of muscle physiology, exercise physiology, cell biology and bioinformatics
Documents to provide to apply:
-Letter of recommendation
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