Sakai Hiromichi, Murakami Chiaki, Takechi Mayumi, Urano Takeshi, Sakane Fumio
Department of Biosignaling and Radioisotope Experiment Interdisciplinary Center for Science Research, Organization for Research and Academic Information, Shimane University Izumo Japan.
Department of Chemistry, Graduate School of Science Chiba University Chiba Japan.
FASEB Bioadv. 2024 Nov 29;7(1):e1481. doi: 10.1096/fba.2024-00134. eCollection 2025 Jan.
Diacylglycerol kinase δ (DGKδ) phosphorylates diacylglycerol to produce phosphatidic acid. Previously, we demonstrated that down-regulation of DGKδ suppresses the myogenic differentiation of C2C12 myoblasts. However, the myogenic roles of DGKδ in vivo remain unclear. In the present study, we generated DGKδ-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 DGKδ-deficient TA muscles. However, DGKδ deficiency did not substantially affect brown adipogenesis, suggesting that Myf5-driven DGKδ deficiency mainly affects muscle development. Notably, skeletal muscle injury induced by a cardiotoxin highly up-regulated DGKδ protein expression, and the DGKδ 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. DGKδ was strongly expressed in myogenin-positive satellite cells around the injured myofibers and centronucleated myofibers. These results indicate that DGKδ 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 DGKδ plays crucial roles in skeletal muscle development, regeneration, and function.
二酰基甘油激酶δ（DGKδ）将二酰基甘油磷酸化以生成磷脂酸。此前，我们证明下调DGKδ可抑制C2C12成肌细胞的肌源性分化。然而，DGKδ在体内的肌源性作用仍不清楚。在本研究中，我们在肌源性因子5（Myf5）基因启动子的控制下生成了DGKδ条件性敲除小鼠，该启动子调节肌生成和棕色脂肪生成。敲除小鼠体重显著减轻，骨骼肌包括胫前肌明显萎缩。此外，DGKδ缺陷型胫前肌中部分肌纤维的厚度减小。然而，DGKδ缺陷对棕色脂肪生成没有实质性影响，这表明Myf5驱动的DGKδ缺陷主要影响肌肉发育。值得注意的是，心脏毒素诱导的骨骼肌损伤使DGKδ蛋白表达高度上调，DGKδ缺陷显著降低了肌纤维厚度、胚胎肌球蛋白重链和肌细胞生成素等肌源性分化标志物的表达水平，以及肌肉再生过程中含有多个中央核的新形成肌纤维的数量。DGKδ在受损肌纤维和中心核肌纤维周围的肌细胞生成素阳性卫星细胞中强烈表达。这些结果表明DGKδ在活化卫星细胞的肌肉再生中起重要作用。此外，高脂饮食喂养的条件性敲除小鼠脂肪量增加且出现葡萄糖不耐受。综上所述，这些结果表明DGKδ在骨骼肌发育、再生和功能中起关键作用。
