Skeletal muscle capillary function: contemporary observations and novel hypotheses

New findings • What is the topic of this review? This review presents the paradigm shift in our understanding of capillary structure and function that has occurred since 1920 (August Krogh's Nobel Prize‐winning work). • What advances does it highlight? The compelling weight of evidence supports the concept that most capillaries support red blood cell (RBC) flux in resting muscle. Increased blood–myocyte flux during contractions thus occurs via elevated RBC flux, velocity and haematocrit in already flowing capillaries, with capillary surface area being recruited along the length of already flowing capillaries. Heart failure, diabetes and sepsis impair blood–myocyte O2 (and glucose) flux by increasing the proportion of non‐RBC/plasma flowing capillaries and compromising the matching of O2 delivery to O2 requirements. The capillary bed constitutes a vast surface that facilitates exchange of O2, substrates and metabolites between blood and organs. In contracting skeletal muscle, capillary blood flow and O2 diffusing capacity, as well as O2 flux, may increase two orders of magnitude above resting values. Chronic diseases, such as heart failure and diabetes, and also sepsis impair these processes, leading to compromised energetic, metabolic and, ultimately, contractile function. Among researchers seeking to understand blood–myocyte exchange in health and the basis for dysfunction in disease, there is a fundamental disconnect between microcirculation specialists and many physiologists and physiologist clinicians. While the former observe capillaries and capillary function directly (muscle intravital microscopy), the latter generally use indirect methodologies (e.g. post‐mortem tissue analysis, 1‐methyl xanthine, contrast‐enhanced ultrasound, permeability–surface area product) and interpret their findings based upon August Krogh's observations made nearly a century ago. ‘Kroghian’ theory holds that only a small fraction of capillaries support red blood cell (RBC) flux in resting muscle, leaving the vast majority to be ‘recruited’ (i.e. to initiate RBC flux) during contractions, which would constitute the basis for increasing surface area for capillary exchange and reducing capillary–mitochondrial diffusion distances. Experimental techniques each have their strengths and weaknesses, and often the correct or complete answer to a problem emerges from integration across multiple technologies. Today, Krogh's entrenched ‘capillary recruitment’ hypothesis is challenged