Capillary-Mitochondrial Oxygen Transport in Muscle: Paradigm Shifts.

When exercising humans increase their oxygen uptake (V̇O₂) 20-fold above rest the numbers are staggering: Each minute the O₂ transport system - lungs, cardiovascular, active muscles - transports and utilizes 161 sextillion (10 ²¹) O₂ molecules. Leg extension exercise increases the quadriceps muscles' blood flow 100-times; transporting 17 sextillion O₂ molecules per kilogram per minute from microcirculation (capillaries) to mitochondria powering their cellular energetics. Within these muscles, the capillary network constitutes a prodigious blood-tissue interface essential to exchange O₂ and carbon dioxide requisite for muscle function. In disease, microcirculatory dysfunction underlies the pathophysiology of heart failure, diabetes, hypertension, pulmonary disease, sepsis, stroke and senile dementia. Effective therapeutic countermeasure design demands knowledge of microvascular/capillary function in health to recognize and combat pathological dysfunction. Dated concepts of skeletal muscle capillary (from the Latin capillus meaning 'hair') function prevail despite rigorous data-supported contemporary models; hindering progress in the field for future and current students, researchers and clinicians. Following closely the 100th anniversary of August Krogh's 1920 Nobel Prize for capillary function this Evidence Review presents an anatomical and physiological development of this dynamic field: Constructing a scientifically defensible platform for our current understanding of microcirculatory physiological function in supporting blood-mitochondrial O₂ transport. New developments include: 1. Putative roles of red blood cell aquaporin and rhesus channels in determining tissue O₂ diffusion. 2. Recent discoveries regarding intramyocyte O₂ transport. 3. Developing a comprehensive capillary functional model for muscle O₂ delivery-to-V̇O₂ matching. 4. Use of kinetics analysis to discriminate control mechanisms from collateral or pathological phenomena.