Background: Diacylglycerol kinases (DGKs) synthesize phosphatidic acid (PA), and PA can activate growth-regulatory mTOR signaling. Results:The isoform of DGK is necessary for a mechanically induced increase in PA-mTOR signaling, and overexpression of DGK induces skeletal muscle hypertrophy. Conclusion: PA synthesized by DGK regulates the mechanical activation of mTOR signaling and hypertrophy. Significance: DGK is a potential target for treating muscle atrophy/wasting.

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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