Fly Homolog of Human Exercise Protein Precursor Regulates Cold Tolerance, Cellular Maintenance

Researchers at University of Michigan (U-M) Medical School and Wayne State University School of Medicine have identified, in fruit flies, a protein that, when missing, makes exercising in the cold harder. Discovered by the team while studying metabolism and the effect of stress on the body, the protein, which they’ve named Iditarod after the long-distance dog sled race across Alaska, was found to act as a regulator of autophagy, exercise performance, and cold resistance. The researchers also found that Iditarod (Idit) is a homolog of the mammalian protein FNDC5, a precursor of the exercise-induced protein irisin.

Research lead Jun Hee Lee, PhD, at the U-M department of molecular and integrative physiology, and colleagues, reported on the study in PNAS, in a paper titled “Iditarod, a Drosophila homolog of the Irisin precursor FNDC5, is critical for exercise performance and cardiac autophagy.” In their paper, the investigators concluded, “Our work suggests an ancient role of an Iditarod/Irisin/FNDC5 family of proteins in autophagy, exercise physiology, and cold adaptation, conserved throughout metazoan species.”

Physical movement is essential for animal life, providing a way to find food, escape from danger, and seek out reproductive partners. “Regular exercise is critical for maintaining physical endurance, not only in mammalian organisms but also in invertebrate organisms such as Drosophila …” they continued. “Therefore, the benefits of exercise are widely conserved across different animal species.”

Mammalian FNDC5 encodes a protein precursor of Irisin, which is important for exercise-dependent regulation of whole-body metabolism, the researchers further noted. And extensive research has found that irisin/FNDC5 is important for producing multiple benefits of exercise, including bone strengthening, and improvements in cognitive function. To date, Irisin/FNDC5 has been studied predominantly in human and mouse cells, and no known homolog has been identified in the genomes of invertebrate species.

Lee et al. were particularly interested in a physiological process called autophagy wherein damaged parts of cells are removed from the body. In screening the Drosophila fruit fly genome to look for autophagy regulators, they found a candidate for regulating this critical housekeeping procedure.

They demonstrated the link between autophagy and the protein, Iditarod, or Idit, by tweaking the genetic makeup of some flies to overactivate autophagy in their eyes. Flies with too much autophagy had massive cell death leading to visible degeneration of the eye. Inactivating the Idit gene restored the normal eye structure, indicating that the Idit gene is involved in the autophagy process.

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, a gene called FNDC5, which is a precursor to the protein irisin, was the top hit,” said Lee. Previous research has shown irisin to be an important hormone involved in producing musculoskeletal and other benefits of exercise in mammals, as well as playing a role in adaptation to cold temperatures. Lee’s lab had an existing interest in exercise as a mild form of bodily stress. “We realized this gene may be also important for exercise and if so, we should be able to detect a similar physiological effect in flies,” said Lee.

Working with the researchers in the lab of Robert Wessells, PhD, at Wayne State University, who have developed a novel way to train fruit flies, the investigators used a sort of fly cliff climber that capitalizes on the insect’s instinct to climb upward out of a test tube.

They found that flies that were bred to lack the Idit gene had impaired exercise endurance, and lacked the improvement typically seen after training. Also of interest, irisin in mammals is known to upregulate thermogenic processes, which is critical for cold resistance. The team found that flies without Idit were also unable to tolerate cold. “Most interestingly, Idit-deficient flies showed several phenotypes that are consistent with the role of Irisin/FNDC5 in mammalian systems, such as defective running endurance, impaired response to exercise training, and decreased cold resistance,” the investigators wrote.

What this tells us, said Lee, is this gene family, present in invertebrates as well as mammals appears to have been conserved throughout evolution and serves an important function. “This work suggests that the Idit/Irisin/FNDC5 family has ancient roles in autophagy, exercise physiology, and cold adaptation, providing insights into the conserved functions and mechanisms of these proteins across metazoan species,” the researchers noted.

“We believe that exercise helps clean the cellular environment through autophagy. When you are exercising hard, there is damage to the muscle and some of the mitochondria will malfunction. The autophagy process becomes activated to clean up any damaged organelles or toxic byproducts, and Idit gene seems important in this process.”

The researchers hope to connect this work to their previous work on exercise and physiological stress. The authors also stated, “Further studies are warranted to examine the mechanistic connection between Idit and autophagy and how these pathways are coordinated during exercise training for stress resistance and endurance extension.”