02/06/2022

Epigenetics and skeletal muscle hypertrophic capacities

This job offer has expired


  • ORGANISATION/COMPANY
    Université Grenoble Alpes
  • RESEARCH FIELD
    Biological sciencesBiology
  • RESEARCHER PROFILE
    First Stage Researcher (R1)
    Recognised Researcher (R2)
    Established Researcher (R3)
    Leading Researcher (R4)
  • APPLICATION DEADLINE
    05/07/2022 00:00 - Europe/Brussels
  • LOCATION
    France › Saint Martin d'Hères
  • TYPE OF CONTRACT
    Temporary
  • JOB STATUS
    Full-time
  • OFFER STARTING DATE
    01/10/2022

OFFER DESCRIPTION

This project aims at finding answers about the role of the epigenome in the control of the hypertrophic capacities of the skeletal muscle and at characterizing the importance of the metabolism as a key actor, through the supply of metabolic groups, necessary to these epigenetic labeling. We will analyze the correlations existing between these marks and the adaptative response of the muscle or its functional capacities at the organism level (dynamic endurance, muscle strength) through access to the preclinical experimental platform of the LBFA. The next step will be to propose some countermeasures to restore a more favorable or appropriate epigenome for a better adaptative response of the skeletal muscle to environmental or microenvironmental stimuli and thus to decrease the percentage of non-responders. At last, it will be considered to measure some of these indicators in human blood samples, such as miRNAs contents as epigenetic regulators to ultimately adapt and customize training programs for athletes of exercise rehabilitation programs in patients.

Skeletal muscle is an essential element in maintaining or improving the health of the healthy or sick individuals. Muscle mass is considered as a significant factor contributing to the quality of life ans is correlated to the survival of Chronic Obstructive Pulmonary Disease (COPD), respiratory disease with systemic consequences, concerning 7.5% of the French population and the 5th cause of deaths in France. Exercise rehabilitation through its anti-inflammatory, anti-oxidative and hypertrophic effects on the muscle, is part of the regular COPD patient care management. However, up to 30% of the patients enrolled in these rehabilitation programs don't get beneficial effects. This bad or non-response may be due to epigenetics modifications (histone acetylation levels related to the inflammation or hypoxic stress associated with the COPD) that could negatively impact the muscle mass control. The objectives of this project are: 1/ the characterization of the role of such factors as regulators of the muscle mass control when exposed to either hypoxia, inflammation or in combination, as environmental factors encountered in the COPD, 2/ characterization of the muscle epigenome (DNA methylation and histone acetylation), with a focus of the different fiber types, using the analysis of the chromatin modifying enzymes and the quantitation of specific microRNAs (myomiRs). Results will be correlated with functional parameters such as dynamic endurance, strength capacities in vivo. Omega-3 fatty acids (DHA), due to their role as regulators of DNA methyltransferases, will be used as a tool to modulate the epigenome in order to confirm its importance in this muscle mass control. This compound could be an interesting way to establish a better epigenetic profile, more appropriate to a proteolysis/proteosynthesis balance compatible with a better muscle mass maintenance in the context of hypoxia and inflammation. Omega-3 fatty acids could be then an additional tool to be included in the COPD patients' management. This project relies on original approaches linking environmental changes and cellular mechanisms that could explain some muscle alterations, with an original preclinical model developed in the laboratory. It will also beneficiate from a scientific network with local and international collaborators, experts in epigenetics.

We have developed an original animal model in the Wistar rat to study the hypertrophic capacities of the skeletal muscle mass that we submitted to various environmental constraints such aas hypoxia/inflammation to mimick some of the main factors encountered by muscle in chronic respiratory diseases. We showed that these hypertrophic capacities are inhibited by inflammation in slow oxidative muscle and merely by hypoxia in fast glycolytic muscle, suggesting that environment plays a leading role in these responses. We also confirmed the involvment of epigenetic mechanisms with a complete restoration of the hypertrophic response win the presence of inhibitors of bromodomains proteins, the latter known to contribute to the reading of such marks. The PhD program will be dedicated to the characterization of the links between theses specific responses and the metabolism and to the analysis of theur functional consequences using physiological measurements (muscle strength in situ, dynamic endurance, muscle typology, etc..). Our goal is to propose ways to to optimize programs to enhance muscle function that could be of interest both in athletes and in patients suffering from chronic diseases affecting muscle function

 

The person recruited will be in charge of the majority of the experiments described in the main project. Among objectives:

- to define the underlying epigenetic mechanisms involved in the control of the muscle mass and the alterations in the muscle epigenome following environmental changes such as hypoxia, exercise, inflammation.

- to characterize the action mechanisms of factors related to lifestyle (nutrition, exercise) on cellular homeostasis and the general health status.

- to understand the phenomenon of non-response of the muscle to training programs and to propose bypassing measures to enhance its performance.

Main activities:

To characterize the alterations of epigenome, the main steps will the as follows:

- literature search and review

- experiments planning

- writing of application for administrative authorizations

- experiments:

- analysis of chromatin alterations using classic approaches (measurement of acetylation, butyrylation and other groups on histones of interest for the control of the muscle function, under various constraints (exercise, hypoxia, nutrition).

- quantification of specific muscle microRNAs (miR-1, miR-29a, miR-29b, miR-133 et miR-206) by RT-PCR on muscle and blood samples to correlate them to the level of hypertrophic response of our model in order to determine criteria specific to good or bad responders operable as predictive factors of training sensitivity of human subjects.

- experiments to modulate activity of chromatin modifying enzymes such as DNA methyltransferases and histone acetylases et deacetylases by fatty acids as regulatory tools to alter chromatin in order to study those consequences on the muscle adaptative response.

- RNAseq and changes in genes expression

- functional measures (dynamic endurance and muscle strength in situ) on animal model

- functional analysis of methylome (Illumina chip) to identify changes on DNA and their links to functional data.

- analysis of the proteosynthesis/proteolysis balance and their related signaling pathways.

- depending on future fundings, translational research on human is also a target objective.

- analysis and interpretation of results

- writing of draft for publications and presentation of the results in seminars or to scientific meetings of interest

- some teaching assignments can be also proposed in intesrested

This project is mainly based on animal models (rodents) and et potentially will include handling of human biological samples. Working during week-end days are also not excluded due to some characteristics in research procedures (treadmill training, muscle strength measurement, cell culture...). Wearing of security and protective individual equipment is mandatory in some areas.

Additional formation during the PhD program can be scheduled, funded by the laboratory



Funding category: Contrat doctoral



PHD Country: France

More Information

Offer Requirements

Specific Requirements

  • Expected skills (priority) :

Strong background in metabolism, exercise physiology, and interest in their fundamental aspects (cellular biology approaches)

  • Trade skills/ expertise

Skillful in basic biochemical analyses are a plus but are not mandatory (training will be provided)

Basic skills in statistical analysis of experimental data

 

  • Personal skills

Master with a research internship (such as master in exercise or sport sciences with major in sport training and/or performance or major in adapted physical activity and health with research internship)

Interest in the role of exercise, environment and nutrition on the muscle function

Know-how :

Be team-oriented, organized and rigorous, proactive, accountable

Master degree in exercise related field (as master STAPS, major in APAS or EOPS) or master degree in physiology or in biology with a research intership

Work location(s)
1 position(s) available at
Université Grenoble Alpes
France
Saint Martin d'Hères

EURAXESS offer ID: 793531
Posting organisation offer ID: 106002

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