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

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