REPTOR and CREBRF encode key regulators of muscle energy metabolism

Pedro Saavedra (), Phillip A. Dumesic, Yanhui Hu, Elizabeth Filine, Patrick Jouandin, Richard Binari, Sarah E. Wilensky, Jonathan Rodiger, Haiyun Wang, Weihang Chen, Ying Liu, Bruce M. Spiegelman and Norbert Perrimon ()
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Pedro Saavedra: Blavatnik Institute, Harvard Medical School
Phillip A. Dumesic: Dana-Farber Cancer Institute
Yanhui Hu: Blavatnik Institute, Harvard Medical School
Elizabeth Filine: Blavatnik Institute, Harvard Medical School
Patrick Jouandin: Institut de Recherche en Cancérologie de Montpellier, INSERM
Richard Binari: Blavatnik Institute, Harvard Medical School
Sarah E. Wilensky: Dana-Farber Cancer Institute
Jonathan Rodiger: Blavatnik Institute, Harvard Medical School
Haiyun Wang: Tongji University
Weihang Chen: Blavatnik Institute, Harvard Medical School
Ying Liu: Blavatnik Institute, Harvard Medical School
Bruce M. Spiegelman: Dana-Farber Cancer Institute
Norbert Perrimon: Blavatnik Institute, Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Metabolic flexibility of muscle tissue describes the adaptive capacity to use different energy substrates according to their availability. The disruption of this ability associates with metabolic disease. Here, using a Drosophila model of systemic metabolic dysfunction triggered by yorkie-induced gut tumors, we show that the transcription factor REPTOR is an important regulator of energy metabolism in muscles. We present evidence that REPTOR is activated in muscles of adult flies with gut yorkie-tumors, where it modulates glucose metabolism. Further, in vivo studies indicate that sustained activity of REPTOR is sufficient in wildtype muscles to repress glycolysis and increase tricarboxylic acid (TCA) cycle metabolites. Consistent with the fly studies, higher levels of CREBRF, the mammalian ortholog of REPTOR, reduce glycolysis in mouse myotubes while promoting oxidative metabolism. Altogether, our results define a conserved function for REPTOR and CREBRF as key regulators of muscle energy metabolism.

Date: 2023
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DOI: 10.1038/s41467-023-40595-1

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