Muscle sympathetic outflow during exercise: a tale of two limbs

Central sympathetic outflow to different skeletal muscle vascular beds (muscle sympathetic nerve activity; MSNA) during exercise is believed to be largely uniform (Ray et al. 1992), leaving the redistribution of blood flow to be regulated by local metabolic factors, including the disruption of neurally mediated vasoconstriction (i.e. functional sympatholysis). However, the assessment of MSNA in humans using microneurographic techniques is limited by the requirement to minimize limb movement and muscle activation. As a result, the majority of prior work has measured MSNA from an inactive limb (e.g. Ray et al. 1992). More recently, advancements in microneurographic signal denoising and sympathetic action potential identification have permitted the examination of the MSNA response in the active limb during exercise (Boulton et al. 2014). These results now provide the capacity to investigate whether sympathetic outflow can be controlled differentially between active and non‐active limbs.

In a recent publication in The Journal of Physiology, Boulton and colleagues (2018) have answered this question, studying the MSNA responses during low‐intensity ipsilateral and contralateral isometric dorsiflexion of the foot. Contractions were performed unilaterally for 4 min at 10% of maximal volitional effort in three randomized conditions: (1) freely perfused contraction and recovery (termed no ischaemia), (2) freely perfused contraction and circulatory occluded recovery (termed post‐exercise ischaemia) and (3) circulatory occluded contraction and recovery (termed continuous ischaemia). Circulatory occlusions were achieved by pneumatic pressure cuff inflation around the upper thigh. MSNA was assessed by identification of negative deflections from the raw neurogram, indicative of sympathetic action potentials, and quantified as spike frequency (spikes min⁻¹). This method differs from conventional burst analysis of the integrated neurogram but is advantageous when recording from the active limb as it allows discrimination of positive deflecting neural activity related to motor activation or muscle spindle and Golgi tendon organ afferent feedback, all of which are active during contraction. The results demonstrated that MSNA to the non‐active leg increased progressively throughout the contraction, becoming significantly elevated from baseline after 2 min, and remained elevated during ischaemia, while MSNA in the active leg increased rapidly (within the first minute of contraction), plateaued during contraction and returned to baseline immediately following contraction, even during ischaemia. As a result, the authors concluded that central command (input from higher order brain regions) was responsible for control of MSNA to the contracting muscles, while activation of metabolically sensitive afferents (muscle metaboreflex) was responsible for MSNA responses in the non‐contracting leg. These results provide strong evidence for the existence of limb‐specific differential control of sympathetic outflow and bring forth novel hypotheses for skeletal muscle blood flow regulation and the integrated control of the sympathetic nervous system during exercise.

The strongest evidence that MSNA to the active limb is influenced predominantly by central command was the rapid increase from baseline in the active limb. Noteworthy, however, was the MSNA activation in the non‐active limb after the first minute of non‐ischaemic exercise, as well as an accentuated response during ischaemic exercise, indicating chemosensitive group III/IV afferent firing in all conditions (though no measurable onset of fatigue given consistent electromyographic recordings). Group III/IV afferent activation has been shown to elicit an inhibitory influence on central motor output (Sidhu et al. 2017), requiring central command to progressively increase over time during non‐ischaemic exercise and during ischaemic exercise to maintain consistent force output. The observations of a plateau in MSNA after the first minute of contraction in the active limb and the similarities in MSNA magnitude between non‐ischaemic and ischaemic exercise do not parallel this expected difference. Perhaps this was related to the use of low‐intensity static dorsiflexion. Whether similar responses are present at higher intensities under stronger muscle metaboreflex activation or during other modes of exercise is unclear. For example, a change in heart rate would indicate a vagal withdrawal (a hallmark of central command), yet this was absent during the exercise protocol.

How these results compare to other modes of exercise is an important issue. Static leg extension at 10% MVC was observed to elicit a reduction in MSNA in the non‐active limb in the first minute of exercise and no change from baseline in the second minute of exercise (Ray et al. 1992). The progressive increase in non‐active limb MSNA in the present study, however, more closely resembles the MSNA responses observed during static handgrip exercise (Ray et al. 1992). Additionally, our laboratory recently compared passive versus unloaded (minimal metaboreflex activation) one‐legged cycling to probe the contributions of central command and demonstrated increases in multi‐unit MSNA burst amplitude, but not occurrence, in the non‐active leg during the first and second minute in the dynamic exercise condition (Doherty et al. 2017). Given that the authors established in a previous investigation that their measure of MSNA using spike frequency was most closely representative of MSNA burst amplitude, as opposed to burst frequency or total MSNA, the absence of a rapid increase in MSNA in the non‐active limb during a static contraction is in contrast to our findings. Whether this reflects differences in the sympathetic response to static and dynamic exercise or muscle mass recruited is unclear.

The most important consideration of the current findings is that the assumption of MSNA measured from the non‐active limb during exercise as reflective of active limb sympathetic outflow can no longer be accepted. An emphasis should now be placed on describing the contribution of sympathetic outflow to functional changes in skeletal muscle vasculature by measuring changes in blood flow patterns in the active and non‐active limb. In addition, basic work needs to resolve how sympathetic outflow can be differentially controlled to the active and non‐active limbs during exercise, whether through limb‐specific or functional organization of sympathetic premotor neurons within the central nervous system or a muscle metaboreflex– central command interaction at the level of the spinal cord.

We would like to strongly re‐emphasize the tremendous contribution that these findings provide in advancing our understanding of differential control of muscle sympathetic outflow during exercise. This should be viewed as a landmark study which should launch more investigations geared towards enhancing our mechanistic understanding of sympathetic nervous system regulation in health and disease.

Additional information

Competing interests

None.

Author contributions

All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

Funding

A.V.I. is supported by a Natural Science and Engineering Research Council of Canada (NSERC) Canada Graduate Scholarship.