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

Area of Science:

• Molecular Biology
• Chronobiology
• Muscle Physiology

Background:

• FBXL21 is a clock-controlled E3 ligase involved in circadian rhythm regulation.
• Its role in tissue-specific circadian physiology and upstream regulatory mechanisms remain unclear.

Purpose of the Study:

• To investigate the upstream regulation and tissue-specific function of FBXL21.
• To identify substrates and understand the mechanism by which FBXL21 controls circadian physiology in skeletal muscle.

Main Methods:

• Identified TCAP as a cytoplasmic substrate of FBXL21 using biochemical assays.
• Investigated FBXL21-TCAP interaction and degradation in skeletal muscle.
• Utilized Psttm mice (Fbxl21 hypomorph) to study in vivo effects.
• Examined the role of GSK-3β in phosphorylating FBXL21 and TCAP.

Main Results:

• TCAP, a sarcomere component, is a circadian substrate of FBXL21 in skeletal muscle.
• FBXL21-TCAP interaction and TCAP degradation are regulated by GSK-3β phosphorylation.
• FBXL21-mediated TCAP degradation is crucial for maintaining skeletal muscle function.
• Psttm mice exhibit skeletal muscle defects and cardiac dysfunction.

Conclusions:

• A GSK-3β-FBXL21 axis controls TCAP degradation via SCF complex formation.
• This pathway is critical for regulating skeletal muscle circadian physiology and function.
• Disruption leads to impaired muscle fiber size, exercise tolerance, and response to atrophy.