A DGKζ-FoxO-ubiquitin proteolytic axis controls fiber size during skeletal muscle remodeling

Science Signaling
Jae-Sung YouTroy A Hornberger

Abstract

Skeletal muscle rapidly remodels in response to various stresses, and the resulting changes in muscle mass profoundly influence our health and quality of life. We identified a diacylglycerol kinase ζ (DGKζ)-mediated pathway that regulated muscle mass during remodeling. During mechanical overload, DGKζ abundance was increased and required for effective hypertrophy. DGKζ not only augmented anabolic responses but also suppressed ubiquitin-proteasome system (UPS)-dependent proteolysis. We found that DGKζ inhibited the transcription factor FoxO that promotes the induction of the UPS. This function was mediated through a mechanism that was independent of kinase activity but dependent on the nuclear localization of DGKζ. During denervation, DGKζ abundance was also increased and was required for mitigating the activation of FoxO-UPS and the induction of atrophy. Conversely, overexpression of DGKζ prevented fasting-induced atrophy. Therefore, DGKζ is an inhibitor of the FoxO-UPS pathway, and interventions that increase its abundance could prevent muscle wasting.

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Citations

Dec 5, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jae-Sung YouTroy A Hornberger
Jan 25, 2019·Journal of Applied Physiology·Craig A Goodman
Jul 17, 2020·Journal of Applied Physiology·Kevin A MurachCory M Dungan
Apr 20, 2019·The Biochemical Journal·Isabel MéridaAntonia Ávila-Flores
Jul 25, 2019·Trends in Endocrinology and Metabolism : TEM·Julie Massart, Juleen R Zierath
Aug 25, 2019·Trends in Endocrinology and Metabolism : TEM·Zhiyong Cheng
Nov 11, 2019·Advances in Biological Regulation·Javier Arranz-Nicolás, Isabel Mérida
Apr 4, 2021·International Journal of Molecular Sciences·Robert SolsonaAnthony Mj Sanchez

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