Continued skeletal muscle performance during prolonged exercise depends on the delivery of oxygen through capillaries to the site of oxidative energy production, the mitochondria. Oxygen delivery is limited in muscle by a number of factors including capillary surface area. Endurance exercise training increases muscle capillarity thus improving oxygen delivery and enabling greater rates of maximal oxygen uptake (VO2max) and improved athletic performance. In skeletal muscle both hypoxia and exercise are known to enhance expression of genes encoding VEGF, a key factor involved in angiogenesis. In the whole animal and in an isolated contracting muscle the potential for exercise induced local hypoxemia, and microcirculatory and fiber type heterogeneities preclude precisely determining the role of hypoxia in regulating mRNA expression. I propose to use a model in which intracellular PO2 can be monitored and manipulated in a single isolated muscle fiber and in which extracellular factors can be precisely controlled. Furthermore, exercise intensity can be varied by electrical stimulation. By elucidating the stimuli effecting VEGF up-regulation in single muscle fibers, a better understanding of how VEGF can be regulated to potentially increase vascularization in patients with chronic renal or heart disease, or to suppress vascularization in tumor masses or in patients susceptible to diabetes-associated retinopathy will be attained.
