Heterogeneity of skeletal muscle perfusion and metabolism.

In this issue of the Journal of Applied Physiology, Mizuno and colleagues (5) report the use of positron emission tomography (PET) in human skeletal muscle (knee extensors) both at rest and at 30 min after exhaustive single-leg cycling. They were able to measure regional perfusion and O2 consumption in five areas situated at an equal distance over a proximal-todistal axis of 12 cm. Their principal conclusion was that there was heterogeneity of hemodynamic variables both at rest and during recovery from exercise, with perfusion and O2 consumption that was lower distally vs. proximally. This formidable illustration of the power of almost noninvasive techniques to gather regional functional information is impressive. Although the spatial resolution may still be coarse compared with the size of functional units of muscle (and we do not yet know that), such methods begin to address one of the most fundamental barriers to the understanding of organ function: heterogeneity. In the muscles, it is the distribution of blood flow (Q̇) in relation to local metabolic rate (O2 consumption; V̇O2) that constitutes the major form of heterogeneity. It is useful to compare this with the lungs, where it is the distribution of perfusion (Q̇) in relation to local alveolar ventilation (V̇A) that is of corresponding concern. We have known for some time that, in lung disease, nonuniform distribution of ventilation-to-perfusion ratios (V̇A/Q̇) is the most important cause of inefficient pulmonary gas exchange and resulting hypoxemia (1). To make this assertion has required the development of methods for measuring, directly or indirectly, all of the causes of inadequate pulmonary gas exchange: V̇A/Q̇ inequality, diffusion limitation of V̇O2, shunting of Q̇ through unventilated alveoli, and diminished ventilation. We are only now developing such methods for skeletal muscle, and Mizuno’s paper is a significant advance in this area. The muscles, similar to the lungs, are subject to a corresponding set of O2 exchange limitations: they are V̇O2/Q̇ inequality, limitation of diffusive transport of O2 from the muscle microcirculation to the mitochondria, shunting of Q̇ through nonnutrient vessels, and diminished total muscle Q̇. Many studies have indirectly suggested that, contrary to most circumstances in the lungs, diffusion limitation is the principal mechanism of O2 unloading limitation, even in healthy controls (2–4, 7), whereas shunts and limited Q̇ appear to be of much less importance. However, the contribution of V̇O2/Q̇ heterogeneity has been largely obscure for lack of direct methods for its measurement. Recently, Richardson and colleagues (6) were able to measure both Q̇ and phosphocreatine depletion in exercising human calf muscle under steady-state conditions using magnetic resonance imaging technology. They took phosphocreatine depletion to represent V̇O2. They found a level of V̇O2/Q̇ inequality that might interfere with O2 exchange to a small degree (8%). Their data, although intriguing, are somewhat preliminary and await better resolution and more direct measures of O2 consumption.