The Metabolic Side of Muscle Atrophy in Space

Preventing muscle atrophy through the activation and upregulation of the mTORC1 protein with amino acids.

Astronaut health is one of the biggest barriers when it comes to space travel. In order to reach sustainable interplanetary travel, we need to keep astronaut health a priority, and find a feasible solution to protein degradation in space.

Human’s just aren’t built for space

But this doesn’t diminish our curiosity to explore.

Why do astronauts spend so much time exercising?

Currently, astronauts undergo 2 hours of intense physical exercise as well as 1 hour of stimulation from an Neuromuscular Electrical Stimulation (NMES) device everyday! These are required in order to keep the muscles active. Uninterrupted protein synthesis is necessary in order to mitigate the slow, but present muscle degradation that occurs in space.

Protein degradation rates increase when muscles aren’t being used. Our weight-bearing muscles work against gravity, and our legs and feet bear the weight. Our musculoskeletal system adapts to the weight and due to microgravity, weight bearing muscles cannot adapt to the new weight upon them. Our bodies are so used to bearing the weight from Earth.

Once astronauts come back to Earth, they are extremely weakened. Muscle can be built up, but lost bone cells are not as easy to get back.

MUSCLE ATROPHY

What?

Muscle atrophy is a loss or weakening of muscle. This is often caused by a lack of movement. For example, living in the space station. 975,000 humans on earth experience muscle atrophy. There are many factors that attribute to muscle atrophy such as age, malnutrition, certain medical conditions and remaining immobile for long periods of time.

Studies have shown that astronauts experience up to a 20 percent loss of muscle mass on space flights lasting five to 11 days. This is why astronauts spend 2–3 hours everyday exercising and stimulating their muscles.

Preventing muscle atrophy through the activation and upregulation of the mTORC1 protein with amino acids.

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The mTORC1 Complex

mTOR is the mechanistic (“mammalian”) target of rapamycin. Rapamycin was discovered in 1964 on the island of Rapa Nui (Easter Island) and was found to have immunosuppressive and anti-tumour properties. mTOR regulates growth, proliferation and survival, and it exists as two complexes. We will be signalling the first complex called mTORC1.

A diagram of the mTORC1 complex

The mTORC1 complex has the mTOR protein itself, as well as raptor (regulated associated protein with mTOR) and the raptor allows the complex to bind to a substrate. There is another protein called mLST8 which stabilized the “kinase loop” within the mTOR complex. There are also two different proteins that have inhibitory roles within the complex (PRAS 40 and DEPTOR — the names aren’t important, it is just important to note that the complex has many different activating and inhibiting functions).

mTOR is regulated at the interface of the lysosomal membrane. The Rheb protein is what activates the mTOR protein and it resides on the surface of the lysosomal membrane. If Rheb is inhibited (by TSC2 or AMPK — check this research paper for a more in-depth showcase of this pathway), mTORC1 will be inhibited as well. There are multiple pathways and regulators intertwined with our mTORC1 protein complex. The one we need to be aware of for protein synthesis is…

Regulation of the Rag site

The Rag isoforms are regulated by GATOR1 → which is regulated/inhibited by GATOR2. CASTOR1 inhibits GATOR2, and Arginine inhibits CASTOR1. Additionally, there’s another inhibitor of GATOR2 which is Sestrin2 (which is inhibited by Leucine). Now, it’s quite convoluted and knowing the specific details is irrelevant.

💡 Realize that Arginine inhibits CASTOR1 → CASTOR1 can’t inhibit GATOR2 → GATOR2 can inhibit GATOR1 → RAG can be activated!!! The same pathway goes for Leucine and Sestrin2.

So you can get the picture ;)

Arginine and leucine can activate mTORC1.
(we need amino acids to activate the mTOR protein!)

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Now that mTORC1 is activated, it’s time for Protein Synthesis

Now that we have a framework to understand the complex regulation of mTORC1, what happens when it’s actually activated?

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The most important function of mTORC1 is that it phosphorylates and activates p70S6K (or p76k). This kinase can inhibits eEF2K (eukaryotic elongation factor 2 kinase) which further inhibits eEF2 through phosphorylation. eEF2 is responsible for elongation of a protein or polypeptide strand within the ribosome. Another thing p76K does is activates eIF4B (eukaryotic initiation factor 4 B), which is again,necessary for polypeptide translation in the ribosome. It can also directly activate the s6 ribosomal subunit in the ribosome.

Here is where we’ve gotten so far in the pathway

As you can see, p70S6K is a crucial signalling hub for protein synthesis, and allows for ribosomal activation and polypeptide translation and synthesis.

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The mTORC1 complex inhibits and regulates more growth factors shown below. The activation of the mTORC1 complex inhibits 4EBP1 which then upregulates the initiation factor eIF4E — which initiates polypeptide translation at the ribosome. Now, this all eventually leads to protein synthesis.

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Summary: mTOR Signalling Effects

Activators:

• Growth factors (ex. Insulin)
• Amino Acids!
• Energy (Glucose → ATP)

Leads to Protein and Nucleotide Synthesis

Inhibitors

• DNA Damage
• AMP activation (not good)

Leads to Autophagy

This is the step-by-step visual showcasing each stage in the metabolic pathway

THE FUTURE

With solving muscle atrophy in space, a door of possibilities open:

• We are going to reduce the overall detrimental affects that occur to an astronaut’s health
• we can leverage our solution to cure metabolic muscular diseases on earth
• Opens a brand new avenue for sustainable space travel
• Optimize for valuable mission time
• Humans will be able to adapt further to foreign environments
• Instead of expensive, external stimulation, we have an internal solution