Abstract
Despite limited regenerative capacity as we age, cardiomyocytes maintain their function in part through compensatory mechanisms, e.g., Vinculin reinforcement of intercalated discs in aged organisms. This mechanism, which is conserved from flies to non-human primates, creates a more crystalline sarcomere lattice that extends lifespan, but systemic connections between the cardiac sarcomere structure and lifespan extension are not apparent. Using the rapidly aging fly system, we found that cardiac-specific Vinculin-overexpression [Vinculin heart-enhanced (VincHE)] increases heart contractility, maximal cardiac mitochondrial respiration, and organismal fitness with age. Systemic metabolism also dramatically changed with age and VincHE; steady state sugar concentrations, as well as aerobic glucose metabolism, increase in VincHE and suggest enhanced energy substrate utilization with increased cardiac performance. When cardiac stress was induced with the complex I inhibitor rotenone, VincHE hearts sustain contractions unlike controls. This work establishes a new link between the cardiac cytoskeleton and systemic glucose utilization and protects mitochondrial function from external stress.
Highlights
IntroductionAging is a complex process associated with the progressive decline of physiological function and is a significant risk factor for cardiovascular disease (CVD); as human a)Present address: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of
Aging is a complex process associated with the progressive decline of physiological function and is a significant risk factor for cardiovascular disease (CVD); as human a)Present address: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of2473-2877/2018/2(3)/036101/15VC Author(s) 2018.036101-2 Sessions et al.APL Bioeng. 2, 036101 (2018)lifespan increases, CVD risk increases.1 With age, the heart remodels extensively, altering extracellular matrix and intracellular structures that decrease elasticity and contractile compliance.2–4 Remodeling creates a feedback loop that further increases systolic pressure and afterload.5,6 Remodeling results in left ventricular wall thickening and impaired myocardial performance.7,8 Counterbalancing these negative processes are compensatory mechanisms that reinforce sarcomeres and the sarcolemma to help manage age-associated increases in heart wall strain
Forced climbing significantly increases energy demand, so these data from flies with cardiac overexpression of Vinculin suggest that benefits are local to the heart and that it significantly increases the activity in aging organisms; it should be noted that activity progressively declines independent of Vinculin expression but that there is prolonged activity for Vinculin heart-enhanced (VincHE) flies consistent with prolonged lifespan
Summary
Aging is a complex process associated with the progressive decline of physiological function and is a significant risk factor for cardiovascular disease (CVD); as human a)Present address: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of. The heart remodels extensively, altering extracellular matrix and intracellular structures that decrease elasticity and contractile compliance.. Remodeling creates a feedback loop that further increases systolic pressure and afterload.. Remodeling results in left ventricular wall thickening and impaired myocardial performance.. Remodeling results in left ventricular wall thickening and impaired myocardial performance.7,8 Counterbalancing these negative processes are compensatory mechanisms that reinforce sarcomeres and the sarcolemma to help manage age-associated increases in heart wall strain Lifespan increases, CVD risk increases. With age, the heart remodels extensively, altering extracellular matrix and intracellular structures that decrease elasticity and contractile compliance. Remodeling creates a feedback loop that further increases systolic pressure and afterload. Remodeling results in left ventricular wall thickening and impaired myocardial performance. Counterbalancing these negative processes are compensatory mechanisms that reinforce sarcomeres and the sarcolemma to help manage age-associated increases in heart wall strain
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