Interorgan communication between iron-deficient skeletal muscle and the failing heart

• Applicant: Bo Mee Chung, Ph.D.
• Subject Area: Cardiology, Angiology ; Animal Physiology and Biochemistry
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 564318588

Iron deficiency (ID) is a prevalent comorbidity in heart failure (HF). Systemic ID disrupts energy metabolism in skeletal muscles, exacerbating skeletal muscle dysfunction. Skeletal muscle wasting and impaired muscle function are also common in HF patients, and serve as an independent predictor of mortality. Our preliminary work has demonstrated that HF affects skeletal muscle iron homeostasis. Thereby we hypothesise that there is the critical interplay between the heart and skeletal muscles in HF. To further investigate the bidirectional relationship between skeletal muscle ID and the heart, we generated a mouse model with skeletal muscle-selective ID by targeting iron regulatory protein 1 and 2 (Irp1/2) using the Cre-loxP system (Skm-Irp1/2 KO). These mice demonstrated impaired adaptation to transverse aortic constriction (TAC)-induced pressure overload, exhibiting worse cardiac function and lower survival rate within three days post-TAC surgery. Histological analyses revealed increased apoptosis and fibrosis in the heart following TAC. Notably, metabolomic analysis indicated a significant reduction in cardiac acetylcholine levels in Skm-Irp1/2 KO mice, observed in both sham and TAC conditions. Further studies aim to understand why cardiac acetylcholine is low in Skm-Irp1/2 KO mice and whether it is responsible for impaired adaptation to pressure overload. As a primary step, we will characterise the cardiac phenotype of these mice after TAC in greater detail. We will specify which cell types in the heart are mostly affected after pressure overload in Skm-Irp1/2 KO mice. To investigate the regulatory mechanisms of cardiac acetylcholine levels, we will assess both the central autonomic nervous system and non-neuronal cardiac cholinergic system in our mouse model. To understand the protective role of cardiac acetylcholine in the pressure-overloaded heart, we will modulate cardiac acetylcholine levels in our mouse model via adeno-associated virus-mediated gene transfer and examine whether it will alter the adaptation to pressure overload. The relevant pathways will be studied using ex vivo and in vitro experimental models, such as myocardial slices and isolated cardiomyocytes. Finally, using plasma proteomics, we will identify myokines, signalling proteins produced by skeletal muscles, that may control cardiac acetylcholine levels or independently worsen cardiac symptoms during pressure overload in Skm-Irp1/2 KO mice. The identified myokines will be assessed in human plasma and we will investigate the possible correlations with skeletal muscle iron status and cardiac symptoms in HF patients. The project will enable the verification of the interorgan communication between iron deficient skeletal muscle and the heart. The study may suggest new diagnostic standards for the detection of skeletal muscle ID and provide preclinical data on the potential therapeutic use of acetylcholine and its regulatory mediators in patients with cardiovascular disease.

• DFG Programme: Research Grants