Deubiquitinating Enzyme USP2 Alleviates Muscle Atrophy by Stabilizing PPAR-γ

Area of Science:

• Molecular Biology
• Metabolic Diseases
• Muscle Physiology

Background:

• Insulin resistance in type 2 diabetes contributes to muscle breakdown and impaired energy metabolism.
• The role of ubiquitin specific peptidase 2 (USP2) in sarcopenia, a common complication of diabetes, is not well understood.
• Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a key regulator of muscle atrophy.

Purpose of the Study:

• To investigate the role of the deubiquitinase USP2 in mitigating muscle atrophy.
• To explore the underlying mechanisms of USP2's action in diabetic and dexamethasone-induced muscle atrophy.

Main Methods:

• Analysis of USP2 expression in skeletal muscles of type 2 diabetes patients and mouse models.
• Utilized knockout mouse models (Usp2 knockout and skeletal muscle-specific Usp2 knockout) to study muscle atrophy.
• Employed adeno-associated virus-mediated gene delivery to restore USP2 in diabetic mouse models.
• Investigated the interaction between USP2 and PPAR-γ using mechanistic analyses.

Main Results:

• USP2 expression was reduced in the skeletal muscles of type 2 diabetes patients and mouse models of muscle atrophy.
• Usp2 deficiency exacerbated muscle loss and functional impairments in diabetic and dexamethasone-treated mice.
• Restoring USP2 in diabetic mice improved muscle mass, performance, and insulin sensitivity.
• USP2 directly deubiquitinated and stabilized PPAR-γ, enhancing insulin signaling and preserving muscle mass.

Conclusions:

• USP2 plays a protective role against muscle atrophy, particularly in the context of type 2 diabetes and dexamethasone-induced conditions.
• The USP2-PPAR-γ axis is crucial for maintaining muscle mass and insulin sensitivity.
• Targeting the USP2-PPAR-γ pathway presents a promising therapeutic strategy for metabolic disorders and sarcopenia.