Incretin-induced changes in the transcriptome of skeletal muscles of fa/fa Zucker rat (ZFR) with obesity, without diabetes

• Published in: International Journal of Obesity 2022-07, Vol.46 (7), p.1311-1318
• Main Authors: Colin, Ides M., Knoops, Bernard, Gérard, Anne-Catherine
• Format: Article
• Language: English
• Subjects: 13/51; 14/63; 38/91; 692/163/2743/393; 692/699/2743/2037; 82/29; Adipocytes; AMP-activated protein kinase; Diabetes; Diabetes mellitus (non-insulin dependent); Endoplasmic reticulum; Epidemiology; Extracellular matrix; Genes; GLP-1 receptor agonists; Glucagon; Glucagon-like peptide 1; Health Promotion and Disease Prevention; Hepatocytes; Insulin; Insulin resistance; Internal Medicine; Kinases; Medicine; Medicine & Public Health; Metabolic Diseases; Muscle contraction; Muscles; Musculoskeletal system; Myofibrils; Obesity; Ontology; Oxidative stress; Phalloidin; Public Health; Signal transduction; Skeletal muscle; Staining; Transcriptomes
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/s41366-022-01114-2

Introduction Glucagon-like peptide-1 receptor agonists (GLP-1ra) are increasingly used in treating type 2 diabetes and obesity. Exendin-4 (Ex-4), a long acting GLP-1ra, was previously reported to decrease oxidative stress in hepatocytes, adipocytes and skeletal muscle cells in obese nondiabetic fa/fa Zucker rats (ZFR), thereby improving insulin resistance. Aim We aimed first to identify Ex-4-induced changes in the transcriptome of skeletal muscle cells in ZFR. Results Ontology analysis of differentially expressed genes (DEGs) in ZFR versus lean animals (LR) showed that the extracellular matrix (ECM) is the first most affected cellular compartment, followed by myofibrils and endoplasmic reticulum (ER). Interestingly, among 15 genes regulated in ZFR versus LR, 14 of them were inversely regulated by Ex-4, as further confirmed by RT-qPCR. Picro-Sirius red histological staining showed that decreased ECM fiber area in ZFR is partially restored by Ex-4. Ontology analysis of the myofibril compartment revealed that decreased muscle contractile function in ZFR is partially restored by Ex-4, as confirmed by Phalloidin histological staining that showed a partial restoration by Ex-4 of altered contractile apparatus in ZFR. Ontology analysis of ER DEGs in ZFR versus LR showed that some of them are related to the AMP-activated protein kinase (AMPK) signaling pathway. Phosphorylated AMPK levels were strongly increased in Ex-4-treated ZFR. Conclusion Altogether, our results suggest that GLP-1ra strongly restructure ECM and reinforce contractile capabilities in ZFR, while optimizing the cellular metabolism through AMPK.