Physical performance declines with aging, promoting a sedentary lifestyle and increasing the risk of obesity, hypertension and diabetes. The capacity of skeletal muscle to sustain activity requires oxygen delivery and metabolite removal. We hypothesize that aging impairs the ability of the microcirculation to supply blood flow to active skeletal muscle fibers by adversely affecting underlying signaling pathways. We have developed the gluteus maximus muscle (a hip extensor essential to locomotion) of the mouse as a model to study how aging affects the control of skeletal muscle blood flow in arteriolar networks. A rapid increase in blood flow in response to contractile activity promotes exercise tolerance by delivering oxygen and removing metabolites, as does the maintenance of hyperemia during exercise and into recovery. With aging, the time course and magnitude of arteriolar dilation and perfusion are severely blunted however the mechanisms underlying these adverse effects on muscle function are unknown.
Aim 1 of this research is to determine how cell-to-cell communication is affected by aging. We will selectively disrupt signaling along arteriolar endothelium and smooth muscle, record the electrical activity of respective cells in vivo, and determine connexin (gap unction) expression with immunolabeling and Real-Time PCR to reveal these mechanisms. Whereas potassium (K+) channels in both smooth muscle and endothelium are integral to vasodilation, the effect of aging on K+ channels in arterioles is unknown.
Aim 2 is to determine how aging effects the functional expression of K+ channels that govern vasodilation using patch clamp recording (and preceding techniques) from freshly-dissociated arteriolar smooth muscle and endothelial cells. Sympathetic nerve activity (SNA) increases with aging and can restrict blood flow to active skeletal muscle, particularly in males.
Aim 3 will determine how aging affects the interaction between SNA and muscle fiber contraction in controlling arteriolar diameter and will do so in light of gender differences. Our long term goal is to define how key signaling pathways that underlie the interaction between muscle fiber contraction and arteriolar dilation are affected by aging. Findings from these studies will provide new and mechanistic insight for developing strategies to ameliorate decrements in muscle blood flow and thereby enhance the quality of life through promoting the ability to engage in physical activity and reduce cardiovascular risks.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086483-05
Application #
8115064
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Reid, Diane M
Project Start
2007-09-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$498,884
Indirect Cost
$147,424
Name
University of Missouri-Columbia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Sinkler, Shenghua Y; Fernando, Charmain A; Segal, Steven S (2016) Differential α-adrenergic modulation of rapid onset vasodilatation along resistance networks of skeletal muscle in old versus young mice. J Physiol 594:6987-7004
Boerman, Erika M; Segal, Steven S (2016) Depressed perivascular sensory innervation of mouse mesenteric arteries with advanced age. J Physiol 594:2323-38
Boerman, Erika M; Everhart, Jesse E; Segal, Steven S (2016) Advanced age decreases local calcium signaling in endothelium of mouse mesenteric arteries in vivo. Am J Physiol Heart Circ Physiol 310:H1091-6
Segal, Steven S (2015) Integration and Modulation of Intercellular Signaling Underlying Blood Flow Control. J Vasc Res 52:136-57
Nance, Michael E; Whitfield, Justin T; Zhu, Yi et al. (2015) Attenuated sarcomere lengthening of the aged murine left ventricle observed using two-photon fluorescence microscopy. Am J Physiol Heart Circ Physiol 309:H918-25
Socha, Matthew J; Boerman, Erika M; Behringer, Erik J et al. (2015) Advanced age protects microvascular endothelium from aberrant Ca(2+) influx and cell death induced by hydrogen peroxide. J Physiol 593:2155-69
Segal, Steven S (2014) Blood flow restriction without sympathetic vasoconstriction in ageing skeletal muscle during exercise. J Physiol 592:4607-8
Hayoz, Sebastien; Bradley, Vanessa; Boerman, Erika M et al. (2014) Aging increases capacitance and spontaneous transient outward current amplitude of smooth muscle cells from murine superior epigastric arteries. Am J Physiol Heart Circ Physiol 306:H1512-24
Domeier, Timothy L; Roberts, Cale J; Gibson, Anne K et al. (2014) Dantrolene suppresses spontaneous Ca2+ release without altering excitation-contraction coupling in cardiomyocytes of aged mice. Am J Physiol Heart Circ Physiol 307:H818-29
Sinkler, Shenghua Y; Segal, Steven S (2014) Aging alters reactivity of microvascular resistance networks in mouse gluteus maximus muscle. Am J Physiol Heart Circ Physiol 307:H830-9

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