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

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 zeta (DGK zeta)-mediated pathway that regulated muscle mass during remodeling. During mechanical overload, DGK zeta abundance was increased and required for effective hypertrophy. DGK zeta not only augmented anabolic responses but also suppressed ubiquitinproteasome system (UPS)-dependent proteolysis. We found that DGK zeta 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 DGK zeta. During denervation, DGK zeta abundance was also increased and was required for mitigating the activation of FoxO-UPS and the induction of atrophy. Conversely, overexpression of DGK zeta prevented fasting-induced atrophy. Therefore, DGK zeta is an inhibitor of the FoxO-UPS pathway, and interventions that increase its abundance could prevent muscle wasting.