LAUSR

Resting humans transport ~ 100 quintillion (10 18 ) oxygen (O 2 ) molecules every second to tissues for consumption. The final, short distance (< 50 µm) from capillary to the most distant mitochondria, in skeletal muscle where exercising O 2 demands may increase 100-fold, challenges our understanding of O 2 transport. To power cellular energetics O 2 reaches its muscle mitochondrial target by dissociating from hemoglobin, crossing the red cell membrane, plasma, endothelial surface layer, endothelial cell, interstitial space, myocyte sarcolemma and a variable expanse of cytoplasm before traversing the mitochondrial outer/inner membranes and reacting with reduced cytochrome c and protons. This past century our understanding of O 2 ’s passage across the body’s final O 2 frontier has been completely revised. This review considers the latest structural and functional data, challenging the following entrenched notions: (1) That O 2 moves freely across blood cell membranes. (2) The Krogh–Erlang model whereby O 2 pressure decreases systematically from capillary to mitochondria. (3) Whether intramyocyte diffusion distances matter. (4) That mitochondria are separate organelles rather than coordinated and highly plastic syncytia. (5) The roles of free versus myoglobin-facilitated O 2 diffusion. (6) That myocytes develop anoxic loci. These questions, and the intriguing notions that (1) cellular membranes, including interconnected mitochondrial membranes, act as low resistance conduits for O 2 , lipids and H + -electrochemical transport and (2) that myoglobin oxy/deoxygenation state controls mitochondrial oxidative function via nitric oxide, challenge established tenets of muscle metabolic control. These elements redefine muscle O 2 transport models essential for the development of effective therapeutic countermeasures to pathological decrements in O 2 supply and physical performance.