Defining the role of succinate signaling in the heart

• Grant number: 24/07724-9
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: March 01, 2025
• End date: February 28, 2030
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Luiz Henrique Marchesi Bozi
• Grantee: Luiz Henrique Marchesi Bozi
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 24/19201-0 - DEFINING THE ROLE OF SUCCINATE IN THE CARDIOPROTECTIVE EFFECT OF BROWN ADIPOSE TISSUE, BP.MS

Abstract

Heart has an extraordinary capacity to cope with several stress conditions, including metabolic and hemodynamic changes. This requires an adaptive response that promotes molecular and structural changes in the heart. Initially, this response is compensatory; however, sustained activation of the cardiac remodeling program impairs heart functionality. Although there is a huge interest in the pharmacological manipulation of this remodeling program, the upstream signals that coordinate the cardiac adaptive/maladaptive remodeling are poorly understood. We recently found that succinate regulates skeletal muscle remodeling through its secretion and ligation of the succinate receptor 1 (SUCNR1). Depending on the physiological context, extracellular succinate levels can rapidly renormalize, or remain elevated. This dynamic regulation of extracellular succinate seems to dictate whether the outcome will be a pro- or anti-pathogenic response. For example, transient elevation of extracellular succinate during exercise training promotes muscle strength gains; while sustained elevation of extracellular succinate is linked to higher risk of cardiovascular disease. A major factor that antagonizes succinate-SUCNR1 signaling is the rate of extracellular succinate sequestration. It has been reported that succinate uptake by brown adipose tissue promotes systemic benefits that are associated with cardiometabolic health. Although these findings indicate succinate as potential mediator of the cardiac remodeling program, the role of succinate signaling in the heart is still unknow. Therefore, we will test in vivo: 1) whether transient elevation of extracellular succinate triggers an adaptive response and protects the heart against ischemia; 2) if sustained elevation of extracellular succinate contributes to pathological cardiac remodeling; and 3) whether brown adipose tissue-mediated extracellular succinate uptake is critical for cardiac homeostasis. Additionally, we will identify which cell populations respond to extracellular succinate and the molecular mechanism behind the succinate-mediated cardiac adaptative and maladaptive responses. (AU)