Zero Gravity, Zero Gain: The Genetics Behind Muscle Loss in Space


Floating through the weightlessness of space, astronauts seldom need to flex their muscles. Slowly diminishing in size and strength, their wasting muscles struggle to support their weight when they return to Earth.1 Space travel’s next frontiers require long-haul odysseys, leaving scientists to contend with the toll of prolonged spaceflight on human anatomy. “Some people lose a ton of bone and muscle, and other individuals lose very little, so that suggests that, not surprisingly, genetic diversity plays a role,” said Henry Donahue, a biomedical scientist at Virginia Commonwealth University. Reporting in npj Microgravity, Donahue and his team placed genetically distinct mice in simulated gravity to explore whether genes influence muscle loss.2 They found that some mice were more susceptible to muscle loss, but they spotted three genes that showed disrupted expression across all strains.

“Clearly this has implications for spaceflight and any future plans on inhabiting any sort of planets, including Mars,” said Stefan Judex, a biomedical engineer at Stony Brook University who was not involved with the work. However, Judex noted, “It must be viewed as a first step simply because this is a mouse study and not a human study.” 

In a previous animal study, scientists searched for the genetic culprits behind muscle weakening, but they used a single strain in order to limit unexplainable variation in the results.3 “That’s like doing a clinical trial on one person,” Donahue noted. Instead, his team used eight genetically distinct mouse strains to explore muscle loss across a diverse population.

On Earth, leg muscles constantly bear the load. Even if you skip leg workout day, they support the body against the tug of gravity whenever people stand, walk, or run. But in the near-zero gravity of space, leg muscles suddenly have little to do. To mimic this abrupt change, Donahue and his colleagues subjected mice to simulated microgravity by strapping tape around their tails and lifting them up just enough to suspend their hindlimbs in the air. After three uninterrupted weeks of simulated microgravity, the team examined the muscles for changes in morphology and gene expression.

To examine muscle morphology in 3D, the researchers used microcomputed tomography. With this technique, X-rays capable of passing through flesh generated scans of the inner anatomy of the hindlimbs. They found that muscles slimmed down in all but two mice strains, suggesting that some strains were resilient to muscle loss.

Next, Donahue and his team tested whether three weeks in simulated space led to changes in gene expression. Three genes stood out, regardless of strain. Judex previously linked a broad stretch of chromosome 5 to muscle loss in mice that underwent simulated microgravity, but he couldn’t identify which specific genes in that region were responsible.4 “It’s exciting to identify specific genes because this is what we as the field ultimately are looking for,” he said. 

Two of the genes, dual specificity phosphatase 8 (Dusp8) and Nogo-B receptor (NgBR), showed lower levels of expression after three weeks compared with that in control mice. Dusp8 protein regulates whether muscles contain fast-twitch fibers for weightlifting or slow-twitch ones for stamina, and NgBR protein regulates the growth of blood vessels around muscles, so changes in their expression could one day offer clues for how the body remodels musculature.5,6 The third gene, cholinergic receptor nicotinic beta 1 subunit (Chrnb1), was expressed at higher levels after microgravity. It codes for part of the acetylcholine receptor that connects nerves with muscles. Although it’s not clear how its overexpression adversely affects muscles, scientists linked it to muscle weakening in previous work.7 

“It’s challenging to interpret what these molecular changes mean,” Judex said. “In the future, these could turn out to be potential drug targets.” Moving forward, Donahue plans to delete each of these genes in mice and monitor the effects on musculature.

The ramifications of spaceflight go beyond muscles. Astronauts tend to feel unwell, dehydrated, and malnourished, which could influence the health of their immune systems as well, Judex noted. Donahue’s team demonstrated that muscle loss might also contribute to weakened immune systems. In one of the mouse strains more susceptible to muscle loss, they detected lower expression of three chemokines that promote muscle growth in addition to coordinating immune cell migration around the body.8

Future genetic studies that elaborate on the link between genes and muscle loss could inform the development of genetic tests. However, even if genetic screens caution astronauts about their risk of muscle loss during spaceflight, Donahue and Judex both independently said that they think astronauts are too determined to visit space to heed those warnings. “Astronauts don’t want to be told that they have this genetic profile that is less than ideal for whatever reason for space travel,” Donahue said. 

Nonetheless, exploring the genetics of muscle loss in simulated microgravity could have implications down here on Earth. It turns out that the muscle loss experienced by astronauts in space is similar to that seen in people with advanced age or in people who are bedridden long-term, Donahue said, so these findings could have broader significance for public health.

References

  1. Comfort P, et al. Effects of spaceflight on musculoskeletal health: A systematic review and meta-analysis, considerations for interplanetary travel. Sports Med. 2021;51(10):2097-2114. 
  2. Zeineddine Y, et al. Genetic diversity modulates the physical and transcriptomic response of skeletal muscle to simulated microgravity in male mice. npj Microgravity. 2023;9(1):86. 
  3. Roberson PA, et al. A time course for markers of protein synthesis and degradation with hindlimb unloading and the accompanying anabolic resistance to refeeding. J Appl Physiol. 2020;129(1):36-46. 
  4. Judex S, et al. Genetic and tissue level muscle-bone interactions during unloading and reambulation. J Musculoskelet Neuronal Interact. 2016;16(3):174-182.
  5. Boyer JG, et al. ERK1/2 signaling induces skeletal muscle slow fiber-type switching and reduces muscular dystrophy disease severity. JCI Insight. 2019;4(10):e127356. 
  6. Miao RQ, et al. Identification of a receptor necessary for Nogo-B stimulated chemotaxis and morphogenesis of endothelial cells. Proc Natl Acad Sci USA. 2006;103(29):10997-11002. 
  7. Khan MAS, et al. Nonsurgically induced disuse muscle atrophy and neuromuscular dysfunction upregulates alpha7 acetylcholine receptors. Can J Physiol Pharmacol. 2014;92(1):1-8. 
  8. Nicholas J, et al. Time course of chemokine expression and leukocyte infiltration after acute skeletal muscle injury in mice. Innate Immun. 2015;21(3):266-274. 

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