Improving exercise tolerance, one of the major goals of physicians treating patients with cardiovascular disease, can be achieved either by improving cardiac output and blood flow to skeletal muscle, or by improving energy metabolism in skeletal muscle, or both. However, less is known regarding specific molecular pathways that might be approached therapeutically to improve exercise tolerance. In the past, we have demonstrated that the adenylyl cyclase type 5 (AC5) knockout (KO) mouse lives one third longer than wild type and is protected against aging induced cardiomyopathy, and the development of heart failure induced by either chronic catecholamine or pressure overload stress. The current project is based on these studies and our preliminary data demonstrating that AC5 KO mice exhibit increased exercise capacity. Our overall hypothesis is that AC5 is a critical enzyme affecting stress resistance and exercise capacity. The goal of this project is to examine mechanisms involved in AC5 inhibition, which could lead to a novel approach to improve exercise performance. There are two major hypotheses: HYPOTHESIS A: AC5 inhibition permits enhanced exercise performance due to improved limb blood flow through enhanced vasodilator mechanisms or angiogenesis, whereas improved cardiac function and cardiac output are less likely mechanisms. HYPOTHESIS B: AC5 inhibition permits enhanced exercise performance due to improved mitochondrial function and/or resistance to oxidative stress and/or improved glucose utilization. The implications for Public Health are clear: improving exercise tolerance will have broad significance for aging, heart disease, most other diseases and even for the young, healthy population.

Public Health Relevance

Improving exercise tolerance, one of major goals of physicians treating patients with cardiovascular disease, can be achieved either by improving cardiac output and blood flow to skeletal muscle, or energy metabolism in skeletal muscle, or both. However, less is known regarding specific molecular pathways that might be approached therapeutically to improve exercise tolerance. The goal of this project is to examine mechanisms involved in AC5 inhibition, which could lead to a novel approach to improve exercise performance. The implications for Public Health are clear: improving exercise tolerance will have broad significance for aging, heart disease, most other diseases and even for the young, healthy population.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL106511-04
Application #
8725726
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Schwartz, Lisa
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Rutgers University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Newark
State
NJ
Country
United States
Zip Code
07103
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Bravo, Claudio; Kudej, Raymond K; Yuan, Chujun et al. (2013) Metabolomic analysis of two different models of delayed preconditioning. J Mol Cell Cardiol 55:19-26
Mottis, Adrienne; Mouchiroud, Laurent; Auwerx, Johan (2013) Emerging roles of the corepressors NCoR1 and SMRT in homeostasis. Genes Dev 27:819-35
Park, Misun; Vatner, Stephen F; Yan, Lin et al. (2013) Novel mechanisms for caspase inhibition protecting cardiac function with chronic pressure overload. Basic Res Cardiol 108:324

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