Effect of muscle-specific ceramide depletion or induction on insulin sensitivity and muscle growth

• Grant number: 20/10619-1
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: September 01, 2021
• End date: May 31, 2022
• Field of knowledge: Health Sciences - Dentistry - Social and Preventive Dentistry
• Principal Investigator: Doris Hissako Matsushita
• Grantee: Thaís Verônica Saori Tsosura
• Supervisor: Scott Andrew Summers
• Host Institution: Faculdade de Odontologia (FOA). Universidade Estadual Paulista (UNESP). Campus de Araçatuba. Araçatuba , SP, Brazil
• Institution abroad: University of Utah (U), United States
• Associated to the scholarship: 19/04182-2 - Assessment of the final steps of insulin signaling, inflammatory pathway, oxidative stress, epigenetic mechanism by DNA methylation and GLUT4 expression in the gastrocnemius muscle of adult rats, offspring of rats with Apical Periodontitis, BP.DR

Abstract

Overnutrition and physical inactivity promote the accumulation of sphingolipids such as ceramides which block insulin signaling and anabolic metabolism. Implementation of pharmacological or genetic interventions to reduce sphingolipid levels in rodents prevents or reverses an impressive array of metabolic pathologies (e.g. insulin resistance, diabetes, steatohepatitis, hypertension, cardiomyopathy, and atherosclerosis). To elucidate the tissue-specific mechanisms through which ceramides contribute to these diseases, we have produced mice allowing for the conditional, cell-type restricted ablation of enzymes required for ceramide biosynthesis or degradation (i.e. serine palmitoyltransferase and dihydroceramide desaturases-1) or degradation (i.e. acid ceramidase). We will apply these tools to dissect the regulatory mechanisms controlling ceramide synthesis and action in skeletal muscle. Aims of the project include the following: to use these novel mouse models to evaluate the effect of muscle-specific ceramide depletion or induction on insulin sensitivity, muscle growth, and genomic/proteomic signatures under conditions of overnutrition and inactivity. Findings obtained from these studies could uncover new nutrient-sensing machinery that modulates insulin sensitivity and muscle growth. Moreover, the translational component could lead to new pharmacological approaches for improving muscle health. (AU)