Scientific background and rationale

The preparation of human space exploration missions, particularly to Mars or lunar bases, requires a detailed understanding of the physiological constraints imposed by extreme environments. One of the critical risks involves the consequences of prolonged exposure to microgravity, potentially combined with a temporary failure of the life support system. In such a scenario, astronauts may face drastic caloric restriction over several days in microgravity. This combination would pose a major threat to their health, physical performance, and mission survival.

Interestingly, hibernating mammals have evolved remarkable physiological mechanisms that allow them to preserve skeletal muscle mass despite prolonged periods of fasting and physical inactivity. Hibernating brown bears exhibit a state of hypometabolism (Bertile et al., 2021), which we have shown to be associated with a specific modulation of TGF-β/BMP signalling pathways (Cussonneau et al., 2021), likely contributing to protein sparing. Moreover, when human skeletal muscle cells are exposed to serum from hibernating bears, they reproduce this signalling profile (Richard et al., 2025) and show a reduced protein turnover (Chanon et al. 2018). These findings suggest that the abundance/composition of circulating factors may change under hypometabolic conditions, thereby regulating signalling pathways for muscle protein sparing.

This project is based on the hypothesis that a hypometabolic state induced by severe caloric restriction in humans could activate protein-sparing mechanisms similar to those observed in hibernating species. These mechanisms may help limit muscle atrophy during inactivity, without significantly impairing muscle strength or functional capacity. They are expected to involve an overall reduction in muscle protein turnover (i.e., synthesis and degradation), along with a reprogramming of inter-organ metabolic crosstalk, mediated by changes in circulating levels of metabolites and hormones regulating protein homeostasis.

Objectives

The overall objective of the PhD project is to identify and characterise the muscle-sparing mechanisms induced by a hypometabolic state in humans. Specific aims include:

(i) To investigate the effects of a hypometabolism induced by severe caloric restriction combined with physical inactivity on TGF-β and BMP signalling pathways in the muscles of healthy volunteers 

(ii) To assess the effect of serum (circulating factors) from these volunteers on cultured human myotubes, and to compare these effects with those induced by hibernating bear serum, focusing on signalling pathways involved in protein metabolism.

Methodologies and Experimental Strategies

The PhD candidate will be involved in a project structured around two already-planned human protocols (first in men, then in women), incorporating multi-omics approaches (transcriptomics, proteomics), as well as in vitro studies using human muscle cell cultures.

PhD Timeline

Year 1 – Focus on Protocol #1 (Male cohort): 

- Implementation of the protocol: spring 2026 ; data (muscle transcriptome/proteome, transcriptome of myotubes exposed to volunteer serum) available by late 2026, at the start of the PhD.

- Transcriptomic and proteomic analysis of TGF-β/BMP pathways in muscle tissues; comparison with brown bear hibernation data (Cussonneau et al., 2021)

- Exposure of human myotubes to serum from volunteers: transcriptome analysis, protein metabolism evaluation, TGF-β/BMP signalling activity

Year 2 – Focus on Protocol #2 (Female cohort):

- Similar analyses in female volunteers (protocol implementation: 2027). Comparison between sexes (Protocol #1 and #2) and with already published bear data (Cussonneau et al. 2021).

- Writing of a first scientific article addressing Objective 1.

- In vitro studies with serum from female volunteers (as above)

Year 3 – Integration, Data Valorisation, and Thesis Writing:

- Integrated analysis of in vitro data with serum proteomics (collaboration: IPHC, Dr. Fabrice Bertile, Strasbourg)

- Comparative analysis of the transcriptomic profiles of human myotubes exposed to serum from volunteers (Ph.D project) to those derived from human myotubes exposed to hibernating bear serum (Richard et al. 2025)

- Writing of remaining scientific articles (Objective 2) and of the PhD manuscript 

Expected Scientific Impact and Dissemination

The project is expected to yield high-impact international publications, including:

- The combined effect of hypometabolism and physical inactivity on TGF-β/BMP pathways in human skeletal muscle

- The effects of human serum on transcriptomic remodelling on protein metabolism and TGF-β/BMP signalling in human myotubes

These findings will deepen our understanding of muscle preservation mechanisms under extreme physiological stress, supporting the development of strategies relevant in space medicine, as well as in clinical settings, such as critical care, aging, or prolonged inactivity.

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For more Information about the topics and the co-financial partner (found by the lab!); contact Directeur de thèse - lydie.combaret@inrae.fr

Then, prepare a resume, a recent transcript and a reference letter from your M2 supervisor/ engineering school director and you will be ready to apply online  before March 13th, 2026 Midnight Paris time!