Skeletal muscle capillary function: contemporary observations and novel hypotheses

Abstract

The capillary bed constitutes a vast surface facilitating 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. Chronic diseases such as heart failure, 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 bases for dysfunction in disease there is a fundamental disconnect between microcirculation specialists and many physiologists and physiologist clinicians. Whereas 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., initiate RBC flux) during contractions which would constitute the basis for increasing capillary exchange surface area 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 by direct observations of capillaries in contracting muscle; something that he and his colleagues could not do. Moreover, in the peer-reviewed scientific literature, application of a range of contemporary physiological technologies including intravital microscopy of contracting muscle, magnetic resonance and near infrared spectroscopy and phosphorescence quenching combined with elegant in situ and in vivo models suggest that the role of the capillary bed, at least in contracting muscle, is subserved without the necessity for de novo capillary recruitment of previously non-flowing capillaries. When viewed within the context of the capillary recruitment hypothesis, this evidence casts serious doubt on the interpretation of those data that are based upon Kroghian theory and indirect methodologies. Thus today a wealth of evidence calls for a radical revision of blood-muscle exchange theory to one in which most capillaries support RBC flux at rest and, during contractions, capillary surface area is “recruited” along the length of previously flowing capillaries. This occurs, in part, by elevating capillary hematocrit and extending the length of the capillary available for blood-myocyte exchange (i.e., longitudinal recruitment). Our understanding of blood-myocyte O2 and substrate/metabolite exchange in health and the mechanistic bases for dysfunction in disease demands no less.

Regulation of Increased Blood Flow (Hyperemia) to Muscles During Exercise: A Hierarchy of Competing Physiological Needs

“…When the microcirculation is visualized using imaging and video techniques in a contracting skeletal muscle, there is marked dilation in all elements of the arteriolar tree, with the most pronounced dilation seen in the smallest arterioles (487,488). Recent evidence also suggests that in many preparations up to ϳ80% of capillaries are perfused at rest, challenging the older idea that capillary recruitment is a major phenomenon contributing to exercise hyperemia and gas exchange in contracting skeletal muscles (363).…”

Programming and regulation of metabolic homeostasis

“…The efforts of many, including Matheau-Costello and colleagues (37,38) and Poole and colleagues (44,45), have established that in the vascular system the capillary surface area is correlated directly with the mitochondrial content and maximal demand for oxidative phosphorylation. Almost everything else related to the role of oxygen is controversial, with widely differing opinions expressed in the literature as to the oxygen dependence of oxidative phosphorylation as well as the oxygen pressure in the cellular and mitochondrial environments.…”

Exercise training in chronic heart failure: improving skeletal muscle O2transport and utilization

“…Contrary to the pioneering model proposed by August Krogh (177,178), compelling contemporary experimental and theoretical evidence has shown that intramyocyte O 2 diffusion distances do not limit mitochondrial O 2 delivery in healthy muscles (therefore negating the notion of intracellular anoxic loci; Refs. 131,246,247). Thus, given that the major resistance to skeletal muscle O 2 diffusion from the RBC to the mitochondria resides at the capillary-myocyte interface (i.e., the so-called "carrier-free region") and the very low and uniform intramyocyte PO 2 values (92,103,256), it may be tempting to speculate that potential alterations in fiber cross-sectional area and/or mitochondrial distribution might not impact D mO 2 significantly in diseased or exercise-trained states.…”