Deciphering Myofilament Modifications in Ischemic Cardiomyopathy

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Project Summary/Abstract Myocardial infarction (MI) is the most common cause of heart failure (HF), but the molecular mechanisms underlying cardiac dysfunction in the post-MI myocardium remain unclear. Moreover, current treatments for HF mainly focus on symptom management after maladaptive ventricular remodeling has occurred. However, a comprehensive understanding of molecular changes at the early-phase (adaptive) remodeling could aid in the development of treatments to prevent late-phase (maladaptive) remodeling and HF. Ventricular remodeling is characterized by alterations in the sarcomere composed of myofilaments flanked by Z-discs. The post- translational modifications (PTMs) of the sarcomeric proteins regulate contractility. Moreover, cardiac contractility highly depends on ATP generation and thus impairment in the ATP-generating processes can rapidly lead to contractile dysfunction. The onset of ischemia is known to be associated with dramatic alterations in cardiac metabolism. PTMs of metabolic enzymes play a key role in regulating the metabolic pathways. Therefore, we hypothesize that concerted dysregulations of sarcomeric and metabolic protein modifications contribute to contractile dysfunction at the early-phase post-MI ventricular remodeling. To test our hypothesis, we will employ a novel systems biology approach enabled by multi-omics integrating top-down proteomics and metabolomics with in vivo and ex vivo functional studies to delineate the molecular mechanism underlying early-phase post-MI ventricular remodeling. This novel multi-omics method allows accurate assessment of changes in the proteome and metabolome from the same heart tissue sample to understand the concerted dysregulation of sarcomeric and metabolic PTMs and metabolites. Moreover, we will use a combination of a large animal (swine) MI model and clinical ischemic cardiomyopathy (ICM) tissues to accelerate translation of our findings to aid in diagnostic and therapeutic interventions in humans. Aim 1 will identify concerted changes in the myofilament and Z-disc proteins in post-MI swine myocardium and relate to contractile dysfunction in both sexes. Aim 2 will determine the metabolic alterations in both proteome and metabolome in the post-MI remodeling. Aim 3 will identify sarcomeric and metabolic markers in ICM patient myocardium and assess their functional consequences in consideration of comorbidities and sex differences. This interdisciplinary and translational/clinical application is highly significant with a strong scientific premise and a novel hypothesis of direct clinical relevance. It will provide a comprehensive study to globally characterize a variety of PTMs in metabolic and sarcomeric proteins as well as the interplay between dysregulation between cardiac metabolism and contractile dysfunction. It has direct translational potential leading to an in-depth understanding of the underlying mechanisms at the early-phase post-MI remodeling and discovery of new sarcomeric and metabolic signatures as a panel of markers for diagnosis of ICM at early-stage.