Diacylglycerol kinase δ is required for skeletal muscle development and regeneration

Diacylglycerol kinase delta (DGK delta) phosphorylates diacylglycerol to produce phosphatidic acid. Previously, we demonstrated that down-regulation of DGK delta suppresses the myogenic differentiation of C2C12 myoblasts. However, the myogenic roles of DGK delta in vivo remain unclear. In the present study, we generated DGK delta-conditional knockout mice under the control of the myogenic factor 5 (Myf5) gene promoter, which regulates myogenesis and brown adipogenesis. The knockout mice showed a significant body weight reduction and apparent mass decrease in skeletal muscle, including the tibialis anterior (TA) muscle. Moreover, the thickness of a portion of the myofibers was reduced in DGK delta-deficient TA muscles. However, DGK delta deficiency did not substantially affect brown adipogenesis, suggesting that Myf5-driven DGK delta deficiency mainly affects muscle development. Notably, skeletal muscle injury induced by a cardiotoxin highly up-regulated DGK delta protein expression, and the DGK delta deficiency significantly reduced the thickness of myofibers, the expression levels of myogenic differentiation markers such as embryonic myosin heavy chain and myogenin, and the number of newly formed myofibers containing multiple central nuclei during muscle regeneration. DGK delta was strongly expressed in myogenin-positive satellite cells around the injured myofibers and centronucleated myofibers. These results indicate that DGK delta has important roles in muscle regeneration in activated satellite cells. Moreover, the conditional knockout mice fed with a high-fat diet showed increased fat mass and glucose intolerance. Taken together, these results demonstrate that DGK delta plays crucial roles in skeletal muscle development, regeneration, and function.