FBXL21 is a clock-controlled E3 ligase modulating circadian periodicity via subcellular-specific CRYPTOCHROME degradation. How FBXL21 regulates tissue-specific circadian physiology and what mechanism operates upstream is poorly understood. Here we report the sarcomere component TCAP as a cytoplasmic substrate of FBXL21. FBXL21 interacts with TCAP in a circadian manner antiphasic to TCAP accumulation in skeletal muscle, and circadian TCAP oscillation is disrupted in Psttm mice with an Fbxl21 hypomorph mutation. GSK-3β phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation. GSK-3β inhibition or knockdown diminishes FBXL21-Cul1 complex formation and delays FBXL21-mediated TCAP degradation. Finally, Psttm mice show significant skeletal muscle defects, including impaired fiber size, exercise tolerance, grip strength, and response to glucocorticoid-induced atrophy, in conjunction with cardiac dysfunction. These data highlight a circadian regulatory pathway where a GSK-3β-FBXL21 functional axis controls TCAP degradation via SCF complex formation and regulates skeletal muscle function.

FBXL21是通过亚细胞特异性CRYPTOCHROME降解来调节昼夜周期的时钟控制E3连接酶。FBXL21如何调节组织特定的昼夜生理机能以及上游的作用机理尚不清楚。在这里，我们报告肌节成分TCAP作为FBXL21的细胞质底物。FBXL21以与骨骼肌中TCAP蓄积相反的昼夜节律方式与TCAP相互作用，并且在具有Fbxl21亚型突变的Psttm小鼠中，昼夜节律TCAP振荡被破坏。GSK-3β使FBXL21和TCAP磷酸化，以激活FBXL21介导的，依赖磷酸腺嘌呤的TCAP降解。GSK-3β抑制或敲低可减少FBXL21-Cul1复合物的形成，并延迟FBXL21介导的TCAP降解。最后，Psttm小鼠显示出明显的骨骼肌缺陷，包括纤维大小受损，运动耐力，抓地力和对糖皮质激素引起的萎缩的反应以及心脏功能障碍。这些数据强调了昼夜节律的调节途径，其中GSK-3β-FBXL21功能轴通过SCF复合物的形成控制TCAP降解并调节骨骼肌功能。