Physical exercise tolerance declines with advancing age and chronic diseases (e.g., chronic heart failure (CHF)) prevalent in the aging community. The degree to which structural and functional alterations within skeletal muscle participate in this effect is unclear. However, there is strong evidence that some facet of the aging process impairs muscle blood flow and its microvascular distribution. This will impair effective oxygen (O2) and substrate delivery and the removal of metabolites. We propose to utilize a unique combination of established (microspheres, intravital microscopy) and novel (phosphorescence quenching measurement of micro vascular partial pressure of O2 (PO2)) methodologies to explore the effects of aging and chronic disease on muscle structure, blood flow and its microvascular distribution and the process of O2 exchange within the microcirculation. Using the rat model of aging and chronic heart failure (CHF), we will test the following hypotheses: 1) Aging reduces perfusion in key limb muscles during both sub maximal and maximal exercise but not at rest. 2) At rest and during sub maximal and maximal muscle contractions, muscle capillary red blood cell (RBC) distribution and velocities become more heterogeneous and this impairs the matching of O2 requirements to O2 delivery (VO2-to-QO2) such that muscle O2 extraction is impaired. 3) The kinetics of muscle O2 exchanges are slowed in aged and diseased muscle and this is associated with increased heterogeneity of capillary RBC distribution and dynamics. These studies will demonstrate the feasibility and validity of obtaining key information at the integrated and isolated muscle level in young and old rats with and without CHF and provide essential mechanistic insights into the role of skeletal muscle vascular dysfunction in the exercise intolerance of the elderly and chronic disease patient populations.
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