| Description |
The purpose of this dissertation was to elucidate the regulation of skeletal muscle oxygen (O2) supply and demand and determine their influence on physical function in health and disease. In the first study, motivated by the theory that heat generated by a muscle attunes O2 supply to metabolic demand, we explored the mechanisms by which moderate heat inhibits a-adrenergic vasocontraction in isolated human skeletal muscle feed arteries. Of note, the previously recognized sympathoinhibitory effect of heat on a1-adrenergic vasocontraction could be prevented by inhibiting the temperature-sensitive TRPV4 ion channels or by endothelial denudation, which indicates that TRPV4 ion channels contribute to this response in an endothelium-dependent manner. In the second study we sought to determine if qualitative changes in mitochondrial O2 consumption contribute to the exercise intolerance exhibited by patients with chronic obstructive pulmonary disease (COPD). Compared to that of healthy controls, permeabilized muscle fibers from the vastus lateralis of patients with COPD exhibited a reduced mitochondrial respiratory capacity that was related to a less-efficient pattern of respiration. Importantly, this altered pattern of respiration, which likely demands more O2 to resynthesize adenosine triphosphate (ATP), was correlated with knee extensor (KE) endurance among patients, suggesting that altered mitochondrial O2 demand contributes to exercise intolerance in COPD. In the third study, inspired by the theory of symmorphosis, which postulates that no single step of the O2 cascade restricts maximal skeletal muscle O2 consumption (VO2max), we investigated the role of O2 supply and demand in determining VO2max in endurance exercise-trained and untrained humans by comparing in vivo (skeletal muscle VO2max, direct Fick) and in vitro (permeabilized muscle fiber mitochondrial VO2max) measures of respiratory capacity. Interestingly, skeletal muscle VO2max of untrained subjects was limited by mitochondrial O2 demand, while in trained subjects, who exhibited a training-induced mitochondrial reserve, VO2max was limited by O2 supply. These findings challenge the concept of symmorphosis by clearly revealing unique constraints to VO2max in untrained and trained humans. In summary, this set of studies helps to elucidate the mechanisms that regulate O2 supply and demand, and clarifies the influence of these factors on physical function in health and disease. |
