Ultra sensitive mTOR in axlotl helps them regrow limbs. Rapamycin stops that ability

It’s one of the mysteries of nature: How does the axolotl, a small salamander, boast a superhero-like ability to regrow nearly any part of its body? For years, scientists have studied the amazing regenerative properties of the axolotl to inform wound healing in humans.

Now, Stanford Medicine researchers have made a leap forward in understanding what sets the axolotl apart from other animals. Axolotls, they discovered, have an ultra-sensitive version of mTOR, a molecule that acts as an on-off switch for protein production. And, like survivalists who fill their basements with non-perishable food for hard times, axolotl cells stockpile messenger RNA molecules, which contain genetic instructions for producing proteins. …

The research found that the axolotl mTOR protein is highly sensitive – the axolotl variety contained a genetic alteration, an expansion in sequence, seen only in axolotl and related salamanders.

Investigating further, Barna and her team collaborated with researchers at University of California, San Francisco to probe the structural differences between axolotl mTOR and mammalian mTOR.

In humans and mice, mTOR (and resulting protein production) activates only when there’s a surplus of nutrients. In other words, mammalian cells use mTOR to make proteins only in the best of times. But in axolotls, after an injury causes cell damage and the breakdown of many molecules, the small rush in loose nutrients is enough to flip the ultra-sensitive mTOR to its active state, turning on the cellular factories that make new proteins.

“Finding this genetic change was a shock – mTOR is an ancient enzyme that is the same in virtually all organisms,” said Zhulyn. “But in axolotls we were seeing evolution of new sequences and a structure that changed its fundamental properties.”

When Barna and her colleagues blocked mTOR with a drug used to prevent protein production and cell division in cancers, the animals were no longer able to regrow limbs. The axolotl mTOR is hypersensitive to stimulation (in this case, injury) but is not more active than mammalian mTOR, they found. That’s key, said Barna – hyperactive mTOR has been linked to tumor growth in many human cancers. Given that the axolotl mTOR doesn’t show hyperactivity, that could explain the remarkable cancer resistance seen in axolotls, she said.

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