The Role of Diacylglycerol Kinase Zeta in Mechanotransduction: A Positive Regulator of Skeletal Muscle Mass

Mechanical loading plays a major role in the regulation of skeletal muscle mass. Defining molecular pathways that links mechanical loading to the control of muscle mass (i.e., mechanotransduction) is of great importance for the development of therapies that can preserve muscle mass during atrophic conditions and, thus, contribute significantly to our health and quality of life. In this study, I first demonstrated that signaling through the mammalian/mechanistic target of rapamycin (mTOR), a well-recognized component of the mechanotransduction pathway, is both necessary and sufficient to alleviate the immobilization-induced decreases in protein synthesis and muscle mass. Having established the importance of mTOR in the maintenance of muscle mass, I began to interrogate how mechanical stimuli activate mTOR signaling, by employing an ex vivo passive stretch model. The results first indicated that mechanical stimuli activate mTOR signaling through a mechanism that involves a direct interaction of phosphatidic acid (PA) with mTOR. Interestingly, the results also revealed that the zeta isoform of diacylglycerol kinase (DGKzeta), which phosphorylates diacylglycerol to generate PA, plays an important role in the mechanically-induced increases in PA and mTOR signaling. Furthermore, it was shown that the overexpression of DGKzeta is sufficient to induce muscle hypertrophy through an mTOR-dependent mechanism that requires DGKzeta kinase activity. Next, by employing an in vivo mechanical overload (OV) model, I demonstrated that DGKzeta plays an essential role in the OV-induced rapid muscle hypertrophy. Surprisingly, it was also demonstrated that DGKzeta not only promotes the activation of mTOR signaling and protein synthesis, but it also attenuates the induction of proteasome-dependent protein degradation and the ubiquitin-proteasome-system (UPS). Subsequent experiments revealed that nuclear DGKzeta is a potent inhibitor of the Forkhead box O transcription factor, which promotes the induction of the UPS. I also found that increased expression of DGKzeta can mitigate various types of muscle atrophy, demonstrating that its therapeutic potential for preventing muscle atrophy. Taken together, this study identifies DGKzeta as a critical component of the mechanotransduction pathway through which mechanical loading promotes the activation of PA-mTOR signaling and protein synthesis, while attenuating the induction of the UPS and protein degradation, to facilitate skeletal muscle hypertrophy.