Research ArticleMUSCLE BIOLOGY

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

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Sci. Signal.  15 May 2018:
Vol. 11, Issue 530, eaao6847
DOI: 10.1126/scisignal.aao6847

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More muscle definition with DGKζ

The failure to maintain muscle mass is a leading risk factor for morbidity and mortality in the elderly and in cancer patients experiencing cachexia. You et al. found that the ζ isoform of diacylglycerol kinase (DGKζ) not only enhanced exercise-induced skeletal muscle growth but also limited muscle wasting in response to denervation or food deprivation. DGKζ exerted these effects independently of its DAG kinase activity. In rodents, DGKζ prevented the activation of the protein-degrading machinery that causes atrophy. Thus, increasing the abundance of DGKζ could accelerate muscle growth in response to exercise and block muscle wasting and its adverse effects.

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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