Edward F. Adolph Distinguished Lecture. Contemporary model of muscle microcirculation: gateway to function and dysfunction.

This review strikes at the very heart of how the microcirculation functions to facilitate blood-tissue oxygen, substrate, and metabolite fluxes in skeletal muscle. Contemporary evidence, marshalled from animals and humans using the latest techniques, challenges iconic perspectives that have changed little over the past century. Those perspectives include the following: the presence of contractile or collapsible capillaries in muscle, unitary control by precapillary sphincters, capillary recruitment at the onset of contractions, and the notion of capillary-to-mitochondrial diffusion distances as limiting O2 delivery. Today a wealth of physiological, morphological, and intravital microscopy evidence presents a completely different picture of microcirculatory control. Specifically, capillary red blood cell (RBC) and plasma flux is controlled primarily at the arteriolar level with most capillaries, in healthy muscle, supporting at least some flow at rest. In healthy skeletal muscle, this permits substrate access (whether carried in RBCs or plasma) to a prodigious total capillary surface area. Pathologies such as heart failure or diabetes decrease access to that exchange surface by reducing the proportion of flowing capillaries at rest and during exercise. Capillary morphology and function vary disparately among tissues. The contemporary model of capillary function explains how, following the onset of exercise, muscle O2 uptake kinetics can be extremely fast in health but slowed in heart failure and diabetes impairing contractile function and exercise tolerance. It is argued that adoption of this model is fundamental for understanding microvascular function and dysfunction and, as such, to the design and evaluation of effective therapeutic strategies to improve exercise tolerance and decrease morbidity and mortality in disease.