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

Author:

Cobb Tyler1,Hwang Irene2,Soukar Michael2ORCID,Namkoong Sim23,Cho Uhn-Soo4,Safdar Maryam1ORCID,Kim Myungjin2,Wessells Robert J.1ORCID,Lee Jun Hee2ORCID

Affiliation:

1. Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201

2. Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109

3. Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea

4. Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109

Abstract

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 throughout metazoan species.

Funder

HHS | NIH | National Heart, Lung, and Blood Institute

HHS | NIH | National Institute on Aging

HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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