Fly Fitness: How the Iditarod Protein Links Exercise, Cold Resistance, and Cell Repair

The gene, called Iditarod, appears to be responsible for exercise’s ability to clear damaged cells.

As the days get shorter and colder in the Northern Hemisphere, it can be harder for those who choose to exercise in the morning to get up and start running. A new study in PNAS identifies a protein that, when missing, makes exercise in the cold much more difficult—at least in fruit lovers.

A team from the University of Michigan Medical School and Wayne State University School of Medicine discovered a protein in flies they named the Iditarod after the famous long-distance dog sled across Alaska while studying metabolism and the effects of stress on the body.

The connection between autophagy and the Iditarod

They were particularly interested in the physiological process called autophagy, in which damaged parts of cells are removed from the body. Screening the fly’s genome, they found a candidate for regulating a critical housekeeping procedure.

They demonstrated a connection between autophagy and the Iditarod, or He went, by tweaking the genetic makeup of some flies to over-activate autophagy in their eyes. Flies with too much autophagy had massive cell death leading to visible degeneration of the eye. Deactivation He went the gene restored the normal structure of the eye, suggesting He went the gene is involved in the autophagy process.

Human connection and the benefits of exercise

The team’s next step was to look for a similar gene, or homolog, in humans.

“When we queried this gene in the human genome, the top hit was a gene called FNDC5, which is a precursor to the irisin protein,” said Jun Hee Lee, Ph.D. from the Department of Molecular and Integrative Physiology of the UM.

Previous research has shown that irisin is an important hormone involved in producing the musculoskeletal and other benefits of exercise in mammals, and also plays a role in adaptation to cold temperatures.

Lee’s lab was interested in exercise as a mild form of physical stress.

“We realized that this gene might also be important for exercise, and if so, we should be able to detect a similar physiological effect in flies,” Lee said.

In collaboration with the team of Dr. Robert Wessells of Wayne State University, who developed a new way to train fruit flies, the investigators used a kind of cliff climber that uses the insect’s instinct to climb out of a test tube.

They found that flies that had been bred to lack them He went gene had impaired exercise endurance and lacked the improvement typically seen after training. In addition, irisin is known to up-regulate thermogenic processes in mammals, which is critical for cold tolerance. Interestingly, it flies without He went they were also unable to tolerate the cold.

What this tells us, Lee says, is this gene family is present in the invertebrates like mammals, they appear to have been conserved throughout evolution and serve an important function.

“We believe that exercise helps clean up the cellular environment through autophagy,” Lee said. “When you exercise hard, muscle damage occurs and some mitochondria fail,” Lee said. “The autophagy process is activated to clean up any damaged organelles or toxic byproducts He went the gene appears to be important in this process.”

Lee hopes to next link this work with their previous work on exercise and physiological stress.

Reference: “Iditarodand Drosophila Irisin precursor homologue FNDC5is critical for exercise performance and cardiac autophagy” by Tyler Cobb, Irene Hwang, Michael Soukar, Sim Namkoong, Uhn-Soo Cho, Maryam Safdar, Myungjin Kim, Robert J. Wessells, and Jun Hee Lee, 18 Sep 2023. Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2220556120

Additional authors include Tyler Cobb, Irene Hwang, Michael Soukar, Sim Namkoong, Uhn-Soo Cho, and Myungjin Kim.