Skeletal muscle cystathionine γ-lyase deficiency promotes obesity and insulin resistance and results in hyperglycemia and skeletal muscle injury upon HFD in mice

Objectives The objective of this study was to investigate whether skeletal muscle cystathionine gamma-lyase (CTH) contributes to high-fat diet (HFD)-induced metabolic disorders using skeletal muscle Cth knockout (Cth(Delta skm)) mice. Methods The Cth(Delta skm) mice and littermate Cth-floxed (Cth(f/f)) mice were fed with either HFD or chow diet for 13 weeks. Metabolomics and transcriptome analysis were used to assess the impact of CTH deficiency in skeletal muscle. Results Metabolomics coupled with transcriptome showed that Cth(Delta 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(f/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(Delta 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 Cth(f/f)+HFD mice. Impaired mitochondria and irregular arrangement in myofilament occurred in Cth(Delta skm)+HFD mice. Omics analysis showed differential pathways enriched between Cth(Delta skm) mice and Cth(f/f) mice upon HFD. More severity in impaired energy metabolism, reduced AMPK signaling, and increased oxidative stress and ferroptosis occurred in Cth(Delta skm)+HFD mice compared to Cth(f/f)+HFD mice. Discussion Our results indicate that skeletal muscle CTH expression dysregulation contributes to metabolism disorders upon HFD.