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  3. Suppression of USP2 in mouse skeletal muscle: a model of oxidative stress in muscle tissue

Suppression of USP2 in mouse skeletal muscle: a model of oxidative stress in muscle tissue

  • Exp Anim. 2025 Jul 19. doi: 10.1538/expanim.25-0032.
Masaki Fujimoto 1,  Tomohito Iwasaki 2,  Marina Hosotani Saito 3,  Naoki Takahashi 4,  Mayuko Hashimoto 5,  Eiki Takahashi 6,  Hiroshi Kitamura 7
Affiliations

Affiliations

  • 1 Laboratories of Disease Models, School of Veterinary Medicine, Rakuno Gakuen University.
  • 2 Department of Food Science and Human Wellness, College of Agriculture, Food and Environment Science, Rakuno Gakuen University.
  • 3 Department of Otolaryngology, University of Texas Medical Branch.
  • 4 Veterinary Anatomy, School of Veterinary Medicine, Rakuno Gakuen University.
  • 5 Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University.
  • 6 Department of Biomedicine, Graduate School of Medical Sciences, Kyushu University.
  • 7 Department of Laboratory Animal Medicine, Tohoku University Graduate School of Medicine.
PMID: 40691076 DOI: 10.1538/expanim.25-0032
Abstract

Emerging evidence indicates that oxidative stress in skeletal muscle is a prerequisite for sarcopenia in diabetic patients. In this study, we show that Ubiquitin-Specific Protease (USP) 2 mitigates the accumulation of Reactive Oxygen Species (ROS) in mature muscle cells. Treatment with ML364, a canonical USP2 Inhibitor, robustly increased mitochondrial ROS in mouse C2C12 myotubes and caused an accompanying increase in the glutathione disulfide (GSSG)/glutathione (GSH) ratio. ML364 also caused mitochondrial damage in C2C12 myotubes, resulting in a reduction in intracellular adenosine triphosphate levels. Correspondingly, under diabetic condition, the muscle-specific Usp2-knockout (msUsp2KO) C57BL/6N mice exhibited a significantly higher lipid peroxide level and GSSG/GSH ratio in skeletal muscle than the control mice. The msUsp2KO mice also exhibited augmented Insulin resistance and glucose intolerance, but showed no obvious deterioration in muscle weight or histology relative to the control mice. However, damaged mitochondria in the soleus muscle were more frequently observed in msUsp2KO mice than in the control mice. Together, these data suggest that USP2 mitigates ROS accumulation and subsequent mitochondrial damage in muscle cells in mice.

Keywords

USP2; diabetes; oxidative stress; skeletal muscle.

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