#apaperaday: Skeletal muscle-on-a-chip in microgravity as a platform for regeneration modeling and drug screening

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Skeletal muscle-on-a-chip in microgravity as a platform for regeneration modeling and drug screening

A paper from @stemcellreports by Kim et al on muscle cultures in space! Yes they sent a muscle bundle culture to the ISS and compared it to a similar experiment done on earth! DOI: 10.1016/j.stemcr.2024.06.010

We have a lot of muscle (about 35-40% of our body mass). Satellite cells can repair muscle when it is damaged. Our muscles operate with Earth’s gravity. In space there is ‘micro-gravity’, which has an impact on muscle maintenance and repair.

Mice sent to space show impaired regeneration and cultured mouse cells in space show impaired differentiation. Astronauts also experience muscle atrophy after space travel. So apparently we need gravity to maintain and properly repair muscle.

This makes space travel challenging and studies are ongoing to see how to counteract the negative impact of micro-gravity on muscle. However, this is difficult to test due to the limited number of people who go into space for extended amounts of time.

Here authors sent a bioreactor with human myoblast cultures in collagen fibrils to the ISS laboratory. The bioreactor was flight compatible and temperature and CO2 levels were controlled and the cells got new medium for a 7 day experiment. A similar experiment was done on earth.

Samples from 2 healthy controls were used. The myotubes in space where shorter, less wide and showed less fusion than those on earth as previously reported for mouse myotubes. RNA was isolated from both cultures after 7 days and RNA-seq was performed.

The impact of gravity was much larger than the difference between the 2 controls. Changes were primarily in mitochondrial pathways and metabolism (upregulated in space), while genes for maintaining muscle mass, extracellular matrix remodeling and regeneration were downregulated.

Authors also performed a proteomics analysis showing increased inflammatory proteins in space and markers for mitochondrial dysfunction. The changes observed in space were similar to those observed with aging, so authors compared the transcripts in space with those of sarcopenia.

There was similarity for the downregulated genes (metabolic changes), but less for the upregulated genes, i.e. genes upregulated in muscle from sarcopenic patients were not up in the myotube cultures in space.

As a countermeasure to the changes, authors also tested 2 potential treatments: a 15-PDGH inhibitor (a potential treatment for sarcopenia) and IGF1, a muscle growth stimulator. Both helped to normalize the space muscle cultures, especially for metabolism and adhesion genes.

However, transcript levels did not normalize fully. Authors mention GDF-15 a lot. This is a protein of the TGF-beta family that seems to be a damage marker with a not very clear function. This partially normalizes with the treatment.

Authors discuss that it is possible to study muscle cultures in space and that effects on muscle growth and regeneration are already apparent after 7 days (good for studying potential treatments). The changes seen also fit with a study into muscles of 59 astronauts.

Authors discuss that there are primarily metabolic changes visible. This is not surprising as there is a shift to type 2 fibers in astronauts during space travel. Authors call this dysfunction – I would call it adaptation to a changed environment.

It is only a problem when you return to gravity and have to ‘readapt’ – losing muscle tissue is much easier than regaining it. This is why you want to try and reduce the muscle loss. Authors conclude their study shows it is possible to study muscle with their cell system.

Of course there are limitations: they could use only 2 control individuals and they could run the experiment only once. As the experiment was done for 7 days, the effect of radiation (increased in space) was not taken into account. For longer space travel this will be a factor.

So as always: more work is needed!