A Novel DGKK-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; however, the mechanisms controlling this process remain illdefined. Here, we identify a novel diacylglycerol kinase ζ (DGKζ)-mediated pathway that regulates muscle mass during remodeling. Specifically, during mechanical overload, DGKζ is elevated and required for effective hypertrophy. Mechanistically, DGKζ not only augments anabolic responses, but it also suppresses ubiquitin-proteasome-system (UPS)- dependent proteolysis. We found that DGKζ is a potent inhibitor of FoxO transcription factor which promotes the induction of the UPS. Interestingly, this function is mediated through a kinase activity-independent, but nuclear localization-dependent, mechanism. During denervation, DGKζ is also increased and required for mitigating the activation of FoxO-UPS and the induction of atrophy. Likewise, when overexpressed, DGKζ prevents fasting-induced atrophy. Therefore, as a potent inhibitor of the FoxO-UPS pathway, DGKζ represents a novel therapeutic target for muscle wasting.