The GSK-3 beta-FBXL21 Axis Contributes to Circadian TCAP Degradation and Skeletal Muscle Function

FBXL21 is a clock-controlled E3 ligase modulating circadian periodicity via subcellular-specific CRYPTO-CHROME degradation. HowFBXL21 regulates tissue-specific circadian physiology and what mechanism operates upstream is poorly understood. Herewereport the sarcomere component TCAPas a cytoplasmic substrate of FBXL21. FBXL21 interactswithTCAP in a circadianmanner antiphasic to TCAP accumulation in skeletalmuscle, and circadian TCAP oscillation is disrupted in Psttm mice with an Fbxl21 hypomorph mutation. GSK-3 beta phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation. GSK-3 beta 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-3 beta-FBXL21 functional axis controls TCAP degradation via SCF complex formation and regulates skeletal muscle function.