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 γ-lyase (CTH) contributes to high-fat diet (HFD)-induced metabolic disorders using skeletal muscle Cth knockout (Cth^Δskm) mice.

Methods: The Cth^Δskm 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^Δskm 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^Δskm+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^Δskm+HFD mice. Omics analysis showed differential pathways enriched between Cth^Δskm 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^Δskm+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.