Dysregulation of KMO in the kynurenine pathway as a key mechanism in neurological disorders induced by exhaustive exercise

• Grant number: 24/11074-0
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: January 03, 2025
• End date: January 02, 2026
• Field of knowledge: Health Sciences - Physical Education
• Principal Investigator: José Rodrigo Pauli
• Grantee: Alisson Luiz da Rocha
• Supervisor: Jorge Manuel Lira Goncalves Ruas
• Host Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil
• Institution abroad: University of Michigan, United States
• Associated to the scholarship: 22/06807-2 - Interrelationship of interleukin-6 and kynurenine pathway in cognitive and behavioral disorders induced by excessive exercise: in vivo and in vitro models, BP.PD

Abstract

Athletes often undergo intense physical training to enhance performance, but maintaining a balance between stimulus and recovery is crucial. Disruption of this balance can lead to adverse outcomes, including a proinflammatory state and major depressive disorder (MDD) associated with exhaustive training, or overtraining. Recent evidence suggests a complex interaction between proinflammatory cytokines, the kynurenine (KYN) pathway, and cognitive/behavioral disorders. The KYN pathway metabolizes tryptophan, generating 'kynurenines' activated in proinflammatory contexts. Dysregulation of this pathway, particularly through kynurenine monooxygenase (KMO), can produce neurotoxic metabolites. Preliminary findings in mice show overtraining induces anxious and depressive behaviors, with upregulated KMO enzyme in the hippocampus, mitigated by interleukin-6 ablation. The presence of KYN pathway enzymes in the peripheral immune system present implications for diseases characterized by inflammation, leading to adverse outcomes in the central nervous system (CNS). This feature underscores a close link between peripheral and central regulation of the KYN pathway in cognitive and behavioral responses. Therefore, the main aim of the project is to investigate the KMO relevance in peripheral immune system cells and provide a molecular signature in the context of exhaustive training. For this, animal models with wild-type and conditional knockout mice for KMO in immune system cells will be utilized. Mice will undergo an exhaustive training protocol, behavior tests, and evaluation of blood-brain-barrier integrity. Additionally, RNA sequencing of the hippocampus will be conducted to provide a molecular signature in the context of exhaustive exercise-induced neurological disturbance. The findings of this study will lead to the discovery of new mechanisms and therapeutic targets to alleviate the impacts of neurological disorders related to excessive exercise.