Insulin resistance, a hallmark of type 2 diabetes, accelerates muscle breakdown and impairs energy metabolism. However, the role of ubiquitin specific peptidase 2 (USP2), a key regulator of insulin resistance, in sarcopenia remains unclear. Peroxisome proliferator–activated receptor γ (PPAR-γ) plays a critical role in regulating muscle atrophy. The role of deubiquitinase USP2 in mitigating muscle atrophy was investigated. Our findings revealed reduced USP2 expression in skeletal muscles of patients with type 2 diabetes. In mouse models of diabetes- and dexamethasone (DEX)-induced muscle atrophy, USP2 expression was downregulated in skeletal muscles. Usp2 knockout exacerbated muscle loss and functional impairment induced by diabetes or DEX. Moreover, skeletal muscle–specific Usp2 knockout further aggravated muscle loss and functional impairment induced by diabetes. Local injection of adeno-associated virus–Usp2 into the gastrocnemius muscles of diabetic mice increased muscle mass and improved skeletal muscle performance and endurance. It enhanced insulin sensitivity in diabetic mice, shown by lower fasting serum glucose and insulin levels and better glucose tolerance. Mechanistic analysis showed USP2 directly interacted with PPAR-γ by deubiquitinating it, stabilizing its protein levels, enhancing insulin signaling and sensitivity, and maintaining muscle mass. Loss of PPAR-γ abolishes the regulatory effects of USP2 on insulin sensitivity and muscle atrophy. MYOD1 activates USP2 transcription by binding to its promoter region. This study demonstrates the protective role of USP2 in mitigating muscle atrophy by stabilizing PPAR-γ through deubiquitination, particularly in models of diabetic and DEX-induced muscle atrophy. Targeting the USP2–PPAR-γ axis may offer promising therapeutic strategies for metabolic disorders and sarcopenia.
Article Highlights
- Ubiquitin specific peptidase 2 (USP2) expression is decreased in patients with type 2 diabetes and mouse models of diabetes-induced muscle atrophy.
- USP2 can enhance insulin sensitivity and improve muscle mass and function in diabetic mice.
- USP2 stabilizes PPAR-γ via deubiquitination to regulate muscle atrophy, uncovering a key mechanism in this process.
- The findings indicate the USP2–PPAR-γ axis has potential as a therapeutic target for metabolic disorders and sarcopenia.
