Skeletal muscle reprogramming of metabolic, ribosomal and developmental pathways contributes to Roux-en-Y gastric bypass-induced adaptation in women

Background: Understanding how skeletal muscle responds to weight loss is crucial for developing targeted strategies to manage obesity and promote sustained improvement in metabolic health. Here, we investigated the molecular mechanisms underlying skeletal muscle reprogramming of gene expression and metabolic activity following Roux-en-Y gastric bypass (RYGB). Methods: Forty-one women were studied before and one year after RYGB surgery. We leveraged multi-omics (DNA methylomics and transcriptomics) and machine learning approaches to complement muscle metabolic analyses and clinical data to identify mechanisms underlying RYGB-induced muscle metabolic reprogramming. Findings: RYGB markedly decreased body weight and fat mass and improved metabolic health. Integrative analysis of vastus lateralis muscle identified 8233 genes with differentially methylated regions and 2173 differentially expressed genes post-RYGB surgery, of which 1197 genes were both differentially methylated and differentially expressed. Promoter hypomethylation was associated with the enhanced expression of transcription factors involved in skeletal muscle development and ribosomal subunits. In contrast, expression of genes encoding mitochondrial proteins decreased despite increases in mitochondrial content and enhanced mitochondrial function in skeletal muscle post-RYGB. Pre-operative muscle OXPHOS capacity, and expression of skeletal muscle hypertrophy and differentiation genes MYOC and EHMT2 were associated with weight loss success. Interpretation: RYGB improves systemic metabolic health and induces sustained skeletal muscle bioenergetic reprogramming characterised by enhanced expression of genes involved in myogenesis and protein translation, but decreased expression of genes involved in mitochondrial metabolism, which may reflect improved mitochondrial quality and function. These findings advance our understanding of skeletal muscle metabolic responses to weight loss and of individual variability in metabolic phenotypes.