Skeletal muscle as a source of IGFBP-2 in a murine model of metabolic dysfunction associated with steatotic liver disease.

Abstract

Introduction and Objectives: Insulin-like Growth Factor Binding Protein (IGFBP)-2 is lower in serum during obesity and metabolic dysfunction. We have previously shown that the decrease in serum IGFBP-2 follows a diminished expression in liver and heart, both associated with the progression of steatotic liver disease. We aimed to identify, in a murine model, the synthesis of IGFBP-2 in extrahepatic tissues involved in metabolic dysfunction: skeletal muscle and adipose tissue. Materials and Patients: Samples of hamstring muscle, and epididymal adipose tissue were obtained from male C57BL/6 mice, fed a high-fat diet supplemented with sucrose and fructose (42g/L) in the beverage during 6 months. All procedures were approved by the Institutional Committee of Care and Use of Laboratory Animals at the School of Medicine, UNAM (FM/DI/005/2022). Four groups were included: Control; Metabolic dysfunction (MD), exhibiting increased bodyweight and adiposity; MD with steatosis (MD+SS); and MD+SS with fibrosis (MD+SS+F). Total protein was isolated in a protease inhibitor cocktail. Protein integrity was assessed by SDS-PAGE. IGFBP-2 was assayed by ELISA. Data was shown as Mean±SD, analyzed by one-way ANOVA; Student´s t test was applied to compare 2 groups. P<0.05 was considered significant. Results: IGFBP-2 expression was 6-fold increased in control skeletal muscle compared to control adipose tissue. In epididymal adipose tissue, IGFBP-2 expression significantly decreased in MD+SS+F compared to Controls, and MD. In contrast, the hamstring showed increased IGFBP-2 expression in mice showing metabolic dysfunction associated with steatotic liver disease: MD+SS and MD+SS+F. The percentage of adiposity significantly increased in MD subjects whereas no changes were observed regarding muscle mass, suggesting hypertrophy might be key. Conclusions: Our results show that metabolic dysfunction (MD) associated with MASLD have a role in inhibiting IGFBP-2 expression in adipose tissue. In contrast, skeletal muscle increases its synthesis. These results suggest a role for skeletal muscle in the reversion of MASLD through IGFBP-2 expression. More studies are needed to identify the roles of skeletal muscle and its hypertrophic state in MASLD.