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

骨骼肌会在各种压力下迅速重塑，由此产生的肌肉质量变化会深刻影响我们的健康和生活质量。我们确定了二酰基甘油激酶ζ（DGKζ）介导的途径，可在重塑过程中调节肌肉质量。在机械超负荷期间，DGKζ丰度增加，是有效肥大所必需的。DGKζ不仅增强了合成代谢反应，而且抑制了泛素-蛋白酶体系统（UPS）依赖性蛋白水解。我们发现DGKζ抑制了促进UPS诱导的转录因子FoxO。此功能是通过一种机制介导的，该机制不依赖于激酶活性，但依赖于DGKζ的核定位。在去神经的过程中 DGKζ丰度也增加了，并且对于减轻FoxO-UPS的激活和萎缩的诱导是必需的。相反，DGKζ的过度表达阻止了禁食引起的萎缩。因此，DGKζ是FoxO-UPS途径的抑制剂，增加其丰度的干预措施可以防止肌肉萎缩。