Yang Shu, Xiong Lijiao, Liao Tingfeng, Li Lixing, Li Yanchun, Kang Lin, Yang Guangyan, Liang Zhen
Department of Geriatrics, The First Affiliated Hospital (Shenzhen People's Hospital), Southern University of Science and Technology, Shenzhen, Guangdong, China.
Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China.
Diabetes. 2025 May 1;74(5):773-786. doi: 10.2337/db24-0375.
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.
胰岛素抵抗是2型糖尿病的一个标志，它会加速肌肉分解并损害能量代谢。然而，泛素特异性蛋白酶2（USP2）作为胰岛素抵抗的关键调节因子，在肌肉减少症中的作用仍不清楚。过氧化物酶体增殖物激活受体γ（PPAR-γ）在调节肌肉萎缩中起关键作用。本研究调查了去泛素化酶USP2在减轻肌肉萎缩中的作用。我们的研究结果显示，2型糖尿病患者骨骼肌中USP2的表达降低。在糖尿病和地塞米松（DEX）诱导的肌肉萎缩小鼠模型中，骨骼肌中USP2的表达下调。敲除Usp2会加剧糖尿病或DEX诱导的肌肉损失和功能障碍。此外，骨骼肌特异性敲除Usp2会进一步加重糖尿病诱导的肌肉损失和功能障碍。向糖尿病小鼠的腓肠肌局部注射腺相关病毒-Usp2可增加肌肉质量，改善骨骼肌性能和耐力。它提高了糖尿病小鼠的胰岛素敏感性，表现为空腹血清葡萄糖和胰岛素水平降低以及葡萄糖耐量改善。机制分析表明，USP2通过去泛素化直接与PPAR-γ相互作用，稳定其蛋白质水平，增强胰岛素信号传导和敏感性，并维持肌肉质量。PPAR-γ的缺失消除了USP2对胰岛素敏感性和肌肉萎缩的调节作用。MYOD1通过结合其启动子区域激活USP2转录。本研究证明了USP2通过去泛素化稳定PPAR-γ在减轻肌肉萎缩中的保护作用，特别是在糖尿病和DEX诱导的肌肉萎缩模型中。靶向USP2-PPAR-γ轴可能为代谢紊乱和肌肉减少症提供有前景的治疗策略。
