Iditarod, a Drosophila homolog of the Irisin precursor FNDC5, is critical for exercise performance and cardiac autophagy

Mammalian FNDC5 encodes a protein precursor of Irisin, which is important for exercise- dependent regulation of whole -body metabolism. In a genetic screen in Drosophila, we identified Iditarod (Idit), which shows substantial protein homology to mouse and human FNDC5, as a regulator of autophagy acting downstream of Atg1/Atg13. Physiologically, Idit-deficient flies showed reduced exercise performance and defective cold resistance, which were rescued by exogenous expression of Idit. Exercise training increased endurance in wild -type flies, but not in Idit-deficient flies. Conversely, Idit is induced upon exercise training, and transgenic expression of Idit in wild -type flies increased endurance to the level of exercise trained flies. Finally, Idit deficiency prevented both exercise- induced increase in cardiac Atg8 and exercise- induced cardiac stress resistance, suggesting that cardiac autophagy may be an additional mechanism by which Idit is involved in the adaptive response to exercise. Our work suggests an ancient role of an Iditarod/Irisin/FNDC5 family of proteins in autophagy, exercise physiology, and cold adaptation, conserved through-out metazoan species.

Automated summary

By studying the fruit fly model, we discovered a new protein called Iditarod, which shows similarity to FNDC5 and plays important roles in autophagy, exercise physiology, and cold adaptation. Deficiency of Iditarod impairs the exercise performance and cold resistance of fruit flies, while overexpression of Iditarod can rescue these functions. Exercise training induces the expression of Iditarod and increases the endurance of fruit flies, indicating the importance of Iditarod in the adaptive response to exercise.