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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL062426-15
Application #
8629551
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
15
Fiscal Year
2014
Total Cost
$386,168
Indirect Cost
$100,547
Name
University of Illinois at Chicago
Department
Type
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Abraham, Dennis M; Davis 3rd, Robert T; Warren, Chad M et al. (2016) β-Arrestin mediates the Frank-Starling mechanism of cardiac contractility. Proc Natl Acad Sci U S A 113:14426-14431
de Tombe, Pieter P; ter Keurs, Henk E D J (2016) Cardiac muscle mechanics: Sarcomere length matters. J Mol Cell Cardiol 91:148-50
Lin, Ying-Hsi; Warren, Chad M; Li, Jieli et al. (2016) Myofibril growth during cardiac hypertrophy is regulated through dual phosphorylation and acetylation of the actin capping protein CapZ. Cell Signal 28:1015-24
Dvornikov, Alexey V; Smolin, Nikolai; Zhang, Mengjie et al. (2016) Restrictive Cardiomyopathy Troponin I R145W Mutation Does Not Perturb Myofilament Length-dependent Activation in Human Cardiac Sarcomeres. J Biol Chem 291:21817-21828
Li, King-Lun; Ghashghaee, Nazanin Bohlooli; Solaro, R John et al. (2016) Sarcomere length dependent effects on the interaction between cTnC and cTnI in skinned papillary muscle strips. Arch Biochem Biophys 601:69-79
Rosas, Paola C; Liu, Yang; Abdalla, Mohamed I et al. (2015) Phosphorylation of cardiac Myosin-binding protein-C is a critical mediator of diastolic function. Circ Heart Fail 8:582-94
Abrol, Neha; de Tombe, Pieter P; Robia, Seth L (2015) Acute inotropic and lusitropic effects of cardiomyopathic R9C mutation of phospholamban. J Biol Chem 290:7130-40
Davis 3rd, Robert T; Simon, Jillian N; Utter, Megan et al. (2015) Knockout of p21-activated kinase-1 attenuates exercise-induced cardiac remodelling through altered calcineurin signalling. Cardiovasc Res 108:335-47
Utter, Megan S; Ryba, David M; Li, Betty H et al. (2015) Omecamtiv Mecarbil, a Cardiac Myosin Activator, Increases Ca2+ Sensitivity in Myofilaments With a Dilated Cardiomyopathy Mutant Tropomyosin E54K. J Cardiovasc Pharmacol 66:347-53
Warren, Chad M; Karam, Chehade N; Wolska, Beata M et al. (2015) Green Tea Catechin Normalizes the Enhanced Ca2+ Sensitivity of Myofilaments Regulated by a Hypertrophic Cardiomyopathy-Associated Mutation in Human Cardiac Troponin I (K206I). Circ Cardiovasc Genet 8:765-73

Showing the most recent 10 out of 256 publications