Combined exercise and metabolic regulation in mice with Nr1d1 deletion in skeletal muscle induced to type 2 diabetes mellitus

• Grant number: 24/22440-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2025
• End date: October 31, 2028
• Field of knowledge: Health Sciences - Physical Education
• Principal Investigator: Adelino Sanchez Ramos da Silva
• Grantee: Jessica Denielle Matos dos Santos
• Host Institution: Escola de Educação Física e Esporte de Ribeirão Preto (EEFERP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 19/11820-5 - Nr1d1 function on the aging-associated Sarcopenia, AP.TEM

Abstract

Type 2 diabetes mellitus (type 2 DM) is a heterogeneous metabolic disease characterized mainly by insulin resistance. Factors such as physical inactivity and increased consumption of high-calorie diets contribute to the development of this pathology. Physical exercise has been shown to be an effective strategy in the prevention and treatment of type 2 DM, as it contributes to glycemic control by increasing insulin sensitivity and reducing insulin resistance. In this context, the nuclear receptor REV-ERB¿, a transcriptional repressor of genes involved in the regulation of circadian rhythms, plays a vital role in the metabolism of glucose, cholesterol, and the inflammatory response. This protein is expressed in several tissues, especially skeletal muscle (SM), acting in mitochondrial biogenesis, oxidative function, modulation of muscle morphology and function. However, the function of REV-ERB¿ in different types of skeletal muscle (SM) has not yet been fully elucidated, especially in the context of the pathogenesis of type 2 DM and adaptations to physical exercise. This study aims to investigate the effects of combined training in knockout (KO) mice for the nuclear receptor subfamily 1 gene, member of the D1 group (Nr1d1), induced to type 2 DM. Homozygous mice floxed for the Nr1d1 gene and conditional KO mice for Nr1d1 males will be induced to type 2 DM by streptozocin and, after 8 weeks on a high-fat or standard diet, will be submitted to a combined training protocol for a further 8 weeks. The methodologies employed include assessment of functional performance, body composition, glucose tolerance test, in vivo analysis of insulin sensitivity, primary cell culture, measurement of mitochondrial respiration, analysis of lipid content, hormonal and inflammatory profile, as well as analysis of gene and protein expression, muscle histology and transcriptome. Statistical analysis will be carried out using two-way analysis of variance (ANOVA), followed by Tukey's test, and the results will be expressed as means ± standard deviation, considering a significance level of p < 0.05. With these analyses, we hope that these data will allow us to identify new molecular targets that can contribute to the treatment of type 2 DM and elucidate the molecular mechanisms associated with combined exercise.