Transcriptomic Regulation of Bedrest-Induced Muscle and Immune System Alterations: Investigating the Role of Long Non-Coding RNA

This research proposal is a continuation of the project “Transcriptomic Regulation of Bedrest-Induced Muscle and Immune System Alterations: Investigating the Role of Long Non-Coding RNA” selected by the European Space Agency in the “Announcement of Opportunity soliciting for Human Research proposals for Bedrest studies”, and funded by the Swedish National Space Agency (SNSA) in the call 2020-R.

Due to the covid pandemic, the bedrest campaigns had to be postponed for 2-years, and therefore additional funding to complete the project is requested through this SNSA 2023-R application.Despite a rather deep understanding of the bedrest-induced phenotypic changes in the skeletal muscle and the immune system, the regulatory mechanisms driving those alterations are only starting to emerge.

In this context, my group has conducted one of the most comprehensive bedrest transcriptomic studies to date.

There we report that as little as 3 minutes per week of muscle activation through resistance exercise during 90 days of bedrest was enough to offset most of the transcriptomic alterations induced by bedrest in the muscle.

However, there were transcripts that were resilient to the countermeasure, suggesting the presence of a residual signature of skeletal muscle disuse.

These data indicate that while bedrest-induced RNA alterations play a significant role directing the phenotypic changes triggered by microgravity in muscle, there must be other(s) regulatory mechanism(s) (e.g., long non-coding RNA) controlling the molecular machinery during bedrest.Bedrest is an optimal platform to test countermeasures to offset the effects of microgravity on the human body.

It has been suggested that artificial gravity (AG) with or without exercise could serve to counteract the alterations induced by microgravity.

However, data to support this notion is currently not available.With this background, we propose a project to define the transcriptomic regulation of skeletal muscle and immune system bedrest-induced alterations, with a particular focus on long non-coding RNA (lncRNA), and to investigate how such regulatory mechanisms are impacted by AG with/without concurrent exercise.In addition, this project will analyze individual variability in response to bedrest, which will expand and complement past work in this area by the current research team.In brief, skeletal muscle and blood samples will be collected from participants from two 60-day bedrest studies using exercise with/without AG as countermeasure (n=48).

The subjects within each study will be divided into 3 groups (bedrest only, bedrest+exercise, bedrest+exercise+AG).

RNA-sequencing will be performed in muscle and immune cells to uncover the tissue-specific transcriptomic signature of bedrest, with specific focus on lncRNA.

A comprehensive phenotypic and functional assessment pre- and post-bedrest will be conducted, including detailed body composition analysis by magnetic resonance imaging, muscle function, bone remodeling, maximal aerobic capacity, and more.

Then, the mechanisms behind individual variability response to bedrest at the molecular, phenotypic, and functional level will be analyzed.

We will also determine the efficacy and mechanisms of exercise and/or AG to combat bedrest-induced changes.Apart from critical information about the molecular mechanisms driving bedrest-induced alterations in the skeletal muscle and the immune system, this project has the potential to identify novel biomarkers for bedrest-induced alterations.

Importantly, these experiments will allow us to evaluate the efficacy of, and mechanisms behind AG countermeasure for microgravity-induced changes.

To guarantee the success of this ambitious project, we have assembled a highly qualified team of specialists with many years of experience in bedrest, space, and integrative physiology research.

The added value generated by this international collaboration is crucial to reach all the goals included in the project.