Dyrk1b promotes autophagy during skeletal muscle differentiation by upregulating 4e-bp1

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• Gain-of-function mutations in Dyrk1b, a regulator of skeletal muscle differentiation, are associated with sarcopenic obesity (SO) and metabolic syndrome (MetS).
• The global gene networks controlled by Dyrk1b during myofiber differentiation remain largely unknown.

Purpose of the Study:

• To elucidate the Dyrk1b-dependent gene network in differentiated C2C12 myofibers using untargeted proteomics.
• To investigate the role of 4e-bp1 as a downstream target of Dyrk1b in skeletal muscle differentiation and its implications in SO.

Main Methods:

• Untargeted proteomics in differentiated C2C12 myofibers to identify Dyrk1b targets.
• CRISPR/Cas9 mediated knockout of Dyrk1b in zebrafish.
• Knockdown and overexpression studies in C2C12 cells.
• Assessment of autophagy and muscle differentiation markers.

Main Results:

• Identification of the translational inhibitor 4e-bp1 as a post-transcriptional target of Dyrk1b.
• Validation of 4e-bp1 as a downstream target of Dyrk1b in zebrafish, where Dyrk1b knockout led to embryonic lethality and reduced myosin expression.
• Demonstration that 4e-bp1 enhances autophagy and mediates Dyrk1b's effects on skeletal muscle differentiation.
• The sarcopenic obesity-associated Dyrk1b mutation (Dyrk1bR102C) impairs muscle differentiation through excessive 4e-bp1/autophagy activation, which can be rescued by reducing autophagic flux.

Conclusions:

• The Dyrk1b-4e-bp1-autophagy axis is a critical pathway in skeletal muscle development.
• Dysregulation of this axis, particularly via the Dyrk1bR102C mutation, contributes to sarcopenic obesity.
• This axis represents a potential therapeutic target for skeletal muscle disorders.