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

Abstract

FBXL21 is a clock-controlled E3 ligase modulating circadian periodicity via subcellular-specific CRYPTO-CHROME 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-3b phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation. GSK-3b 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-3b-FBXL21 functional axis controls TCAP degradation via SCF complex formation and regulates skeletal muscle function.

Cost-effective circadian mechanism: rhythmic degradation of circadian proteins spontaneously emerges without rhythmic post-translational regulation

“…Follow-up expansion of our theoretical framework, in concert with more extensive experimental studies on time-specific protein degradation, is warranted for a comprehensive understanding of circadian turnover dynamics and phenotypic implications ( Wirianto et al, 2020 ; Zhou et al., 2015 ). A recent report suggests that about one thousand human genes with circadian expression encode the targets, transporters, and metabolizing enzymes of drugs ( Ruben et al, 2018 ).…”

The Role of Cullin-RING Ligases in Striated Muscle Development, Function, and Disease

“…Fbxl3 also binds to Tcap but does not modulate its protein levels. Loss of Fbxl21 functionality in mutant skeletal muscles disrupted the circadian oscillation of Tcap in a Gsk-3β-dependent manner, leading to smaller fiber sizes and reduced skeletal and cardiac muscle function [112].…”

The Skeletal Muscle Circadian Clock Regulates Titin Splicing Through RBM20

“…Most recently, our lab has identified titincap (Tcap), a protein that anchors the titin filament at the Z-line by binding titin's Z1Z2 domain, as a clock-controlled gene (27,28). Titin-cap's protein levels change over time of day with highest levels during the active phase (29,30). These observations suggest a model in which titin protein could be exchanged daily, likely in sync with times at which Tcap protein is lowest.…”