Impact of leucine supplementation on HDAC4 expression and activity in ZSF1 rat cardiac remodeling (HFpEF model)

• Grant number: 22/04133-4
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Effective date (Start): October 01, 2022
• Effective date (End): September 30, 2023
• Field of knowledge: Biological Sciences - Morphology - Anatomy
• Principal Investigator: Anselmo Sigari Moriscot
• Grantee: Paula Ketilly Nascimento Alves
• Supervisor: Volker Adams
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Research place: Technische Universität Dresden (TU Dresden), Germany
• Associated to the scholarship: 21/05827-7 - Effect of leucine on the expression of miR-299a and HDAC4 in the skeletal muscle of rats submitted to hind limb immobilization: implications for the control of muscle mass, BP.DD

Abstract

Heart Failure with preserved ejection fraction (HFpEF, approximately 50% of all heart failure (HF) cases) is a complex syndrome, with high morbidity and mortality rates. This form of HF is frequently seen in patients suffering from co-morbidities associated with the metabolic syndrome, namely obesity, hypertension, diabetes mellitus and hyperlipidemia, suggesting that HFpEF is a systemic disease that includes heart features. The prevalence of HFpEF is increasing worldwide, including Brazil. A suitable HFpEF animal model is the ZSF1 rat model mimicking changes seen in the human situation like progressive diastolic dysfunction, concentric cardiac hypertrophy, preserved left ventricular ejection fraction and exercise intolerance. Therefore, this model has been used for testing new pharmaceutical substances. A promising therapy that has been applied in HF models is nutritional intervention by leucine supplementation. Leucine has been shown to reduce myocardial damage and the risk of death in patients with HEpEF. However, the mechanisms by which leucine supplementation protects the heart is not fully understood and a better molecular understanding is warranted. Recently our group demonstrated for the first time that leucine supplementation strongly attenuates the increased expression of HDAC4 in response to hindlimb immobilization, suggesting another way in which leucine protects skeletal muscle (Alves et al., 2020). Besides promoting skeletal muscle atrophy, HDAC4 also induces cardiac hypertrophy and fibrosis. Therefore, leucine supplementation could be a promising strategy to protect cardiac function by HDAC4 inhibition in HFpEF. Thus, aim of the project is to characterize the impact of leucine supplementation on cardiac and skeletal muscle function in HFpEF, with a specific focus on HDAC4 regulation. For that, 30 ZSF1 rats will be used and randomly divided into three groups: ZSF1-lean group, ZSF1-obese group, and the ZSF1-obese/Leu group. The heart, soleus, and tibialis anterior muscles will be used for further functional, tissue, and molecular analysis including echocardiography, immunofluorescence and mRNA and protein levels. (AU)