Skeletal muscle cystathionine ?-lyase deficiency promotes obesity and insulin resistance and results in hyperglycemia and skeletal muscle injury upon HFD in mice
In the present study, we explored whether skeletal muscle cystathionine ?-lyase (CTH) contributes to high-fat diet (HFD)-induced metabolic disorders using skeletal muscle Cth knockout (Cth?skm) mice. Metabolomics coupled with transcriptome showed that Cth?skm mice displayed impaired energy metabolism and some signaling pathways linked to insulin resistance (IR) in skeletal muscle although the mice had normal insulin sensitivity. HFD led to reduced CTH expression and impaired energy metabolism in skeletal muscle in Cth-floxed mice (Cthf/f) mice. CTH deficiency and HFD had some common pathways enriched in the aspects of amino acid metabolism, carbon metabolism, and fatty acid metabolism. Cth?skm+HFD mice exhibited increased body weight gain, fasting blood glucose, plasma insulin, and IR, and reduced glucose transporter 4 and CD36 expression in skeletal muscle compared to Cthf/f+HFD mice. Impaired mitochondria and irregular arrangement in myofilament occurred in Cth?skm+HFD mice. Omics analysis showed differential pathways enriched between Cth?skm mice and Cthf/f mice upon HFD. More severity in impaired energy metabolism, reduced AMPK signaling, and increased oxidative stress and ferroptosis occurred in Cth?skm+HFD mice compared to Cthf/f+HFD mice. Our data indicate that skeletal muscle CTH expression dysregulation contributes to metabolism disorders upon HFD. Overall design: The WT and CSE?skm mice were fed with HFD or chow from 4-weeks old for 13 weeks. The mice were sacrificed under deep anesthesia at 17-weeks old. Gastronemius was obtained for RNA-seq analysis.