The capacity for physical activity is diminished with aging. Though largely attributed to sarcopenia (reduced mass and quality of skeletal muscle), little is known of how aging influences muscle blood flow and oxygen supply. Our working hypothesis is that the ability of the microcirculation to supply skeletal muscle fibers is impaired with aging, with adverse consequences on muscle function. Based upon the burgeoning development of genomic strategies in murine systems, the C57BL/6 mouse will be developed here as a model. Our goal is to define the changes that occur in the structure and function of the microcirculation in skeletal muscle that occur with aging. Vascular conductance in muscle appears diminished with aging; however, the underlying structural and functional adaptations are unresolved. Therefore, using vascular casting and histology, Aim 1 is to determine how micro vascular topology and morphology are altered by aging. Little is known of how aging influences the interaction between muscle fiber contraction, metabolic vasodilation, and oxygen delivery. Therefore, Aim 2 is to determine the effect of aging on arteriolar tone, reactivity and capillaty perfusion. Using the cremaster muscle preparation, intravital microscopy will determine whether responses to endothelium-dependent or -independent vasodilators are impaired and thereby define how microvascular responsiveness to muscle fiber contraction may be blunted. During exercise, both the redistribution of cardiac output to active skeletal muscle and the maintenance of microvascular perfusion pressure are governed through sympathetic nerve activity. Whereas changes in sympathetic neuroeffector pathways have been inferred, the effect of aging on the ability of sympathetic nerves to govern arterioles and venules is unknown. Therefore, Aim 3 is to determine the effect of aging on neural control of microvascular resistance and capacitance. We will test whether aging impairs sympathetic vasoconstriction, distinguish whether such changes are due to altered release of neurotransmitter vs. depressed responsiveness of microvascular smooth muscle cells, and determine whether the effects of aging on vasomotor responses to neurotransmitters are unique to catecholamines. Defining these key relationships in control (C57BL/6) mice will generate mechanistic hypotheses focused on how aging influences the cellular and molecular signaling pathways that dictate microvascular structure and function. Our long-term goal is to apply physiological genomics towards developing novel strategies for minimizing the adverse consequences of aging on muscle function and physical activity and to thereby preserve the quality of life.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG019347-02
Application #
6621219
Study Section
Geriatrics and Rehabilitation Medicine (GRM)
Program Officer
Dutta, Chhanda
Project Start
2002-02-01
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2006-05-31
Support Year
2
Fiscal Year
2003
Total Cost
$229,204
Indirect Cost
Name
John B. Pierce Laboratory, Inc.
Department
Type
DUNS #
010139210
City
New Haven
State
CT
Country
United States
Zip Code
06519
Long, Jennifer B; Segal, Steven S (2009) Quantifying perivascular sympathetic innervation: regional differences in male C57BL/6 mice at 3 and 20 months. J Neurosci Methods 184:124-8
Segal, Steven S (2005) Regulation of blood flow in the microcirculation. Microcirculation 12:33-45
Soderberg, Kelly A; Payne, Geoffrey W; Sato, Ayuko et al. (2005) Innate control of adaptive immunity via remodeling of lymph node feed arteriole. Proc Natl Acad Sci U S A 102:16315-20
Bearden, Shawn E; Segal, Steven S (2005) Neurovascular alignment in adult mouse skeletal muscles. Microcirculation 12:161-7
Looft-Wilson, Robin C; Payne, Geoffrey W; Segal, Steven S (2004) Connexin expression and conducted vasodilation along arteriolar endothelium in mouse skeletal muscle. J Appl Physiol 97:1152-8
Bearden, Shawn E; Payne, Geoffrey W; Chisty, Alia et al. (2004) Arteriolar network architecture and vasomotor function with ageing in mouse gluteus maximus muscle. J Physiol 561:535-45
Payne, Geoffrey W; Madri, Joseph A; Sessa, William C et al. (2004) Histamine inhibits conducted vasodilation through endothelium-derived NO production in arterioles of mouse skeletal muscle. FASEB J 18:280-6
Payne, Geoffrey W; Madri, Joseph A; Sessa, William C et al. (2003) Abolition of arteriolar dilation but not constriction to histamine in cremaster muscle of eNOS-/- mice. Am J Physiol Heart Circ Physiol 285:H493-8