Muscular USP2 is dispensable for MASLD-associated disorders in the liver and skeletal muscle in mice

We investigated the roles of muscular Ubiquitin-Specific Protease (USP) 2 in the integrity of liver and muscle in metabolic dysfunction-associated steatotic liver disease (MASLD) using a mouse model. Choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 8 weeks caused apparent steatosis and fibrosis in the liver of C57BL/6N mice, whereas serum triglyceride and total Cholesterol levels were reduced. Although CDAHFD promoted steatosis, inflammation, and fibrosis in the liver, it failed to affect the tissue mass of the gastrocnemius and soleus muscles. Muscle-specific USP2 knockout (musUsp2KO) mice and control Usp2fl/fl mice exhibited the CDAHFD-induced changes in blood lipids, liver weight, and liver histology at a comparable level. Similarly, soleus muscle weight, diameter of muscle fibers, and physical activity were indistinguishable between musUsp2KO mice and Usp2fl/fl mice in CDAHFD-induced MASLD condition. Comprehensive RNA Sequencing and subsequent RT-qPCR analyses indicated that USP2 deficiency potentiated C1qtnf3 expression in the muscle of MASLD mice. Accordingly, chemical inhibition of USP2 elevated C1qtnf3 mRNA in C2C12 myotubes. Application of recombinant C1QTNF3 stimulated mitochondrial biogenesis in C2C12 cells. Considering that USP2 mitigates mitochondrial oxidative stress, induction of C1QTNF3 might compensate for the depletion of USP2 in skeletal muscle.

C1QTNF; MASH; MASLD; USP2; fatty liver; muscle atrophy.