Effects of endurance exercise on plasma GDF-15 levels and the crosstalk between skeletal muscle and endocrine pancreas

• Grant number: 24/04705-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: June 01, 2024
• End date: May 31, 2026
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal Investigator: Antonio Carlos Boschiero
• Grantee: Marcos Divino Ferreira Junior
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 21/04664-7 - Molecular mechanisms involved in pancreatic beta cell dysfunction and death in Diabetes Mellitus: strategies for the inhibition of these processes and restoration of the insular mass, AP.TEM

Abstract

GDF-15, or Growth and Differentiation Factor 15, has been considered a biomarker of cellular stress. This protein can be produced and secreted by various organs such as the liver, kidneys, and skeletal muscle. Recently, it was reported that in vitro contractile stimulation of muscle cells increased the gene and protein expression of GDF-15, as well as its content in the culture supernatant of these cells. The same dynamics were verified in the muscle tissue and plasma of exercised humans. Human pancreatic islets induced to be an in vitro model of DM-1, and pancreatic islets from DM-1 individuals, exhibited lower concentrations of GDF-15. The administration of GDF-15 in these islets promoted a significant improvement in its function. Exogenous administration of GDF-15 reduced the incidence of DM-1 in NOD animals by 53%. However, the function of GDF-15, released during physical exercise, as a possible mediator of communication between skeletal muscle and the pancreas, as well as the likely repercussions of this crosstalk in the context of DM-1, has not yet been investigated.Objectives: To evaluate the effect of endurance physical exercise on insulin secretion, and the pathways associated with cell survival/death in pancreatic islets from C57BL/6 mice and humans induced to DM-1 in vitro. Analyze the role of possible molecules/signals of crosstalk between muscle and pancreatic tissue, considering GDF-15 released into the bloodstream during physical exercise.Strategy: healthy animals will undergo 8 weeks of endurance training. We will evaluate the serum concentration of GDF-15 immediately, 3h, 6h, 12 and 24h after the last training session. The serum from these animals will be used to incubate beta cell lines exposed to the cocktail with pro-inflammatory cytokines (in vitro model of DM-1). We will also use antibodies against GDF-15 in beta cells incubated with serum from trained animals. We will evaluate cell viability and expression of proteins related to cell death and survival pathways. The same experiments will be carried out on human beta cell lines and human pancreatic islets with serum from individuals trained in endurance physical exercise. We will also include an animal model of DM-1 (induced by multiple low doses of streptozotocin). A group of diabetic animals will receive antibodies against GDF-15 through intravenous administration during the last weeks of training. At the end of the training, we will evaluate glycemic control (GTT, ITT and insulinemia), the plasma level of GDF-15 will be measured, and the pancreas will be collected for histological evaluation. Expected results: demonstrate that endurance physical exercise may be able to minimize the harmful effects induced by DM-1 on glycemic control, testing GDF-15 as one of the modulators of this phenomenon. Furthermore, we hypothesize that the serum from these animals can reduce the mortality rate of pancreatic beta cells with DM-1 induced by pro-inflammatory cytokines, and that the neutralization of GDF-15 with the use of specific antibodies reduces the capacity of serum from trained animals and humans to protect beta cells from the deleterious effects induced by DM-1.