Muscle‐specific functional sympatholysis in humans

Neural factors play a pivotal role in controlling circulatory function during exercise. Normally, sympathetic nerves cause vasoconstriction in most vascular beds. Skeletal muscle sympathetic nerve activity usually increases in response to exercise, but so too does muscle blood flow. This is somewhat paradoxical, but it is known that the normal vasoconstriction caused by sympathetic nerves at rest is blunted during exercise, and this phenomenon has been termed ‘functional sympatholysis’. However, functional sympatholysis has not been a consistent finding, as different studies have reported variable results ranging from well-preserved α-adrenergic vasoconstriction to complete inhibition of vasoconstriction during exercise. Differences in methods, species and interpretation of the study results are likely to account for at least some of the discrepancies. In addition, functional sympatholysis in muscle may also be affected by or manifest differently depending on the composition of fibre types, but this topic has remained sparsely investigated in humans to date. In humans, no muscle-specific differences in the modulation of α-adrenergic tone was found in four heads of the quadriceps femoris muscle group measured by positron emission tomography (Heinonen et al. 2013). Reductions and increments in blood flow in response to intra-arterial infusions of the α-adrenergic agonist noradrenaline and the antagonist phentolamine were always similar in the four different muscles investigated at rest and during exercise (Heinonen et al. 2013). In addition to muscle, significant changes in blood flow also occurred in other tissues of the limb (adipose tissue and bone), resulting in the major finding that inhibition of α-adrenergic tone disturbs the distribution of blood flow and oxygen extraction in the exercising human limb by increasing blood flow, especially around inactive muscle fibres and non-muscle tissues. Thus, sympathetic vasoconstriction ensures an optimal distribution of blood flow to the most activated muscles. In humans, it is known that blood flow heterogeneity is linked to muscle activation; however, a precise link to muscle fibre type in this pattern has not been clearly elucidated. Of the four quadriceps muscles, the vastus intermedius has a higher expression of oxidative (type I) fibres (Johnson et al. 1973; Edgerton et al. 1975), but the overall distribution (∼45–65% type I) across the four muscles is relatively homogeneous. In 1994, Thomas and co-workers reported that α-adrenergic tone is modulated differently in oxidative and glycolytic muscles in animals (Thomas et al. 1994). Specifically, functional sympatholysis was shown to occur preferentially in glycolytic rather than oxidative skeletal muscles in rats (Thomas et al. 1994). In humans, the soleus and gastrocnemius muscle of the calf exhibit disparate fibre types, with the soleus consisting mostly (∼80%) of oxidative slow-twitch muscle fibres and the gastrocnemius of ∼50–55% glycolytic fast-twitch fibres (Johnson et al. 1973; Edgerton et al. 1975; Trappe et al. 2001). These were also the muscles that Masahiro Horiuchi and colleagues (Horiuchi et al. 2014) compare in this issue of the Experimental Physiology in order to examine whether skeletal muscle composed of a greater proportion of glycolytic fibres is more sensitive to functional sympatholysis as found in rodents. They provide the first human evidence to support the early animal study by reporting that sympatholysis indeed occurs to a greater extent in the gastrocnemius than the soleus at light exercise loads. Sympathetic activation was evoked in the study by a cold pressor challenge at rest and during plantar flexion exercise, and although no pharmacological tools were applied to provide deeper mechanistic insights, this research is timely, because emerging evidence suggests that the efficacy of oxygen supply versus demand, which is probably also affected by sympathetic nervous activity, may differ among muscles and distinct fibre types not only in health, but also in disease (Koga et al. 2014). The findings of Horiuchi et al. (2014) help to integrate the findings from animal studies by demonstrating fibre type specificity of sympatholysis, suggesting a similar pattern of type II fibre sensitivity to sympatholysis previously undetected across muscle groups with homogeneous fibre type distribution (Heinonen et al. 2013). The study provides new avenues for future research in order to gain deeper understanding of human muscle-specific vascular tone regulation, and having this study as a background, it would be worth investigating whether observed differences are more pronounced in disease states associated with an overactive sympathetic nervous system, as well as the changes induced by exercise training (Jendzjowsky & Delorey, 2013). Readers are invited to give their opinion on this article. To submit a comment, go to: http://ep.physoc.org/letters/submit/expphysiol;99/2/344. The author thanks Professor Robert Boushel, from Åstrand Laboratory, Swedish School of Sport and Health Science, Stockholm, Sweden, for insightful discussions and scientific guidance around the topic over the years, as well as review of the manuscript.