Project 3 examines adaptive changes in the metabolic support of contractile function subsequent to sarcomere remodeling. This project relates to the central theme of the program project, by investigating metabolic remodeling in hearts with altered myofilament sensitivity to Ca[2+], and the potential to reciprocally influence myofilament activity through altered metabolic signaling. The overall objective is to determine if myofilament modifications induce adaptive, maladaptive, and/or cardioprotective shifts in metabolic pathways. The work examines whether the pathophysiological stress induces reciprocal changes in both metabolic activity, through AMPK-linked shifts in competing modes of substrate oxidation for energy production, and contractile function, through resulting affects of acyl-derivatives on contractile function via phosphorylation of sarcomeric proteins. The primary hypothesis is that: Chemical modifications of the contractile/regulatory proteins, specifically within troponin and possibly the regulatory myosin light chain, influence metabolic phenotype which reciprocally effects sarcomere activity by altering the chemical environment of the cytosol. We propose three specific aims: 1) Determine the balance between fatty acid oxidation and storage in pressure overloaded, transgenic mouse hearts that express the fetal/neonatal isoform of troponin I, ssTnl, an apparent model of stress resistance, and test for attenuation of potentially maladaptive changes in oxidative metabolism that occur during pressure overload cardiac. 2) Elucidate alterations in the metabolic support of contractile function at baseline and during B-adrenergic stress, in mouse heart models of myofilament modifications that will or will not develop familial hypertrophic cardiomyopathy (FHC), and also display altered AMPK activation 3) Determine the metabolic responses to rescue of hearts from TG mice with high Ca[2+] sensitivity and FHC, by crossing with a mouse heart model of desensitized myofilaments.
These aims will be accomplished though a unique approach, combining NMR determinations of metabolic flux and enzyme expression with experiments on myofilament function and proteomics. The experimental plan will enable study of the three-way link between metabolic flux, AMPK activation, and Ca[2+] sensitivity of the sarcomeres in the pathogenesis of cardiomyopathy.

Public Health Relevance

The research investigates poorly understood mechanisms that may contribute to the development of heart failure. Specifically, results will define the changes in how the diseased heart muscle consumes and stores fuels, such carbohydrates and fats, in response to impaired cardiac function and the reciprocal effects of such metabolic changes on contraction of heart muscle.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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University of Illinois at Chicago
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