Physical inactivity is a major independent risk factor for cardiovascular disease (CVD) and is now considered one of the leading contributors to premature death (Blair, 2009). Rates of physical inactivity continue to increase along with health care costs to treat CVD. Despite these disturbing trends, the mechanisms by which a sedentary lifestyle leads to CVD are not fully known. CVD is associated with increased sympathetic nervous system activity and overactivity of a brainstem region known as the rostral ventrolateral medulla (RVLM) (Sved et al., 2003;Guyenet, 2006). Sympathoexcitatory responses to direct activation of the RVLM are enhanced in sedentary versus physically active animals (Mueller, 2007). These data suggest that a sedentary lifestyle may contribute to the development of CVD by increased sensitivity of RVLM neurons. Our long term goal is to understand the central sympathetic mechanisms by which physical inactivity contributes to the development of CVD. This is an important clinical, economic and public health care problem. The overall objective of this application is to determine mechanisms by which physical inactivity (versus physical activity) increases sympathetic output from neurons in the RVLM. The central hypothesis is that enhanced sympathoexcitation observed in sedentary animals is due to increased NMDA receptor-mediated excitation of RVLM neurons that regulate sympathetic activity to functional distinct organs involved in blood pressure regulation. We plan to test our central hypothesis and accomplish the overall objectives of this application by pursuing the following specific aims: 1) Determine the extent to which sedentary versus physically active conditions alter reflex sympathoexcitation to functionally distinct target organs involved in blood pressure regulation. 2) Examine the effect of sedentary versus physically active conditions on activation of spinally-projecting sympathoexcitatory neurons of the RVLM. 3) Ascertain the mechanisms by which NMDA receptor mediated transmission in the RVLM may enhance sympathoexcitation in sedentary versus physically active rats. Our proposal provides a compelling rationale to understand the mechanisms by which a sedentary lifestyle may predispose individuals to CVD. We expect to establish at the end of this five year project the extent to which physical inactivity impacts regulation of a group of neurons that are critical to normal and pathophysiological increases in sympathetic nervous system activity. The results of this proposal will provide a greater understanding of the detrimental effects of a sedentary lifestyle on cardiovascular health and define potential therapeutic targets for the treatment and prevention of CVD. These studies may improve the lives of individuals who are unable or unwilling to exercise by 1) the development of new treatment options for CVD;2) increasing public awareness of the detrimental effects of a sedentary lifestyle;and 3) indirectly reducing escalating health care costs associated with physical inactivity.

Public Health Relevance

The proposed research is relevant to public health because a sedentary lifestyle is a major risk factor for cardiovascular disease and is now considered the number one cause of preventable death. This proposal examines an important group of neurons within the brain that we propose contribute to the increased incidence of cardiovascular disease in sedentary individuals. This contribution is significant because it is expected to provide knowledge that could be used to develop therapeutic strategies that will counteract the effects of a sedentary lifestyle on cardiovascular diseases that are currently burdening the population and our health care system.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Thrasher, Terry N
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Wayne State University
Schools of Medicine
United States
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Huereca, Daniel J; Bakoulas, Konstandinos A; Ghoddoussi, Farhad et al. (2018) Development of manganese-enhanced magnetic resonance imaging of the rostral ventrolateral medulla of conscious rats: Importance of normalization and comparison with other regions of interest. NMR Biomed 31:
Dombrowski, Maryetta D; Mueller, Patrick J (2017) Sedentary conditions and enhanced responses to GABA in the RVLM: role of the contralateral RVLM. Am J Physiol Regul Integr Comp Physiol 313:R158-R168
Lalande, Sophie; Mueller, Patrick J; Chung, Charles S (2017) The link between exercise and titin passive stiffness. Exp Physiol 102:1055-1066
Mueller, Patrick J; Clifford, Philip S; Crandall, Craig G et al. (2017) Integration of Central and Peripheral Regulation of the Circulation during Exercise: Acute and Chronic Adaptations. Compr Physiol 8:103-151
Subramanian, Madhan; Mueller, Patrick J (2016) Altered Differential Control of Sympathetic Outflow Following Sedentary Conditions: Role of Subregional Neuroplasticity in the RVLM. Front Physiol 7:290
Wang, Hanjun; Case, Adam J; Wang, Wei-Zhong et al. (2016) Redox Signaling and Neural Control of Cardiovascular Function. Oxid Med Cell Longev 2016:7086018
Mischel, Nicholas A; Subramanian, Madhan; Dombrowski, Maryetta D et al. (2015) (In)activity-related neuroplasticity in brainstem control of sympathetic outflow: unraveling underlying molecular, cellular, and anatomical mechanisms. Am J Physiol Heart Circ Physiol 309:H235-43
Subramanian, Madhan; Holt, Avril G; Mueller, Patrick J (2014) Physical activity correlates with glutamate receptor gene expression in spinally-projecting RVLM neurons: a laser capture microdissection study. Brain Res 1585:51-62
Mischel, Nicholas A; Llewellyn-Smith, Ida J; Mueller, Patrick J (2014) Physical (in)activity-dependent structural plasticity in bulbospinal catecholaminergic neurons of rat rostral ventrolateral medulla. J Comp Neurol 522:499-513
Llewellyn-Smith, Ida J; Mueller, Patrick J (2013) Immunoreactivity for the NMDA NR1 subunit in bulbospinal catecholamine and serotonin neurons of rat ventral medulla. Auton Neurosci 177:114-22

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