Glucose restriction enhances oxidative fiber formation: A multi-omic signal network involving AMPK and CaMK2

Skeletal muscle is a highly plastic organ that adapts to different metabolic states or functional demands. This study explored the impact of permanent glucose restriction (GR) on skeletal muscle composition and metabolism. Using Glut4m mice with defective glucose transporter 4, we conducted multi-omics analyses at different ages and after low-intensity treadmill training. The oxidative fibers were significantly increased in Glut4m muscles. Mechanistically, GR activated AMPK pathway, promoting mitochondrial function and beneficial myokine expression, and facilitated slow fiber formation via CaMK2 pathway. Phosphorylation-activated Perm1 may synergize AMPK and CaMK2 signaling. Besides, MAPK and CDK kinases were also implicated in skeletal muscle protein phosphorylation during GR response. This study provides a comprehensive signaling network demonstrating how GR influences muscle fiber types and metabolic patterns. These insights offer valuable data for understanding oxidative fiber formation mechanisms and identifying clinical targets for metabolic diseases. [Display omitted] •A multi-omic atlas illustrates skeletal muscle adaptation to glucose restriction•Glucose restriction promotes the formation of oxidative muscle fibers•Glucose restriction alters protein phosphorylation in skeletal muscle•Perm1 may synergize AMPK and CaMK signaling under glucose restriction Comp: Metabolomics; Omics; Genomics; Proteomics