Motor activity could not occur without the assistance of the sympathetic nervous system (SNS) due to its control of autonomic functions that distribute energy resources to support the metabolic requirements of working muscles. The SNS is activated centrally together with the motor system, and its activity is modulated according to the magnitude of the motor output (feed-forward). In addition, the SNS responds to feedback signals from muscle afferents activated in response to alterations in the local chemical milieu (25).
The demand for blood flow from the muscle may vary more than 50-fold during working conditions; the main support of the motor activity by the SNS is through its action on the cardiovascular system to potentiate the heart pump and redistribute the blood flow to perfuse the working muscles. In addition, the SNS augments energy supply by promoting glycogenolysis and lipolysis in the liver and adipose tissues, supports the increase in ventilation by dilating the upper airways, and enhances the dissipation of heat from the working muscles. The SNS also modulates several functions of the skeletal muscle cell, such as ionic fluxes through the membrane, acetylcholine release from the motor end plate, calcium (Ca2+) release and reuptake from the sarcoplasmic reticulum, and glucose and protein metabolism. These mechanisms are schematically summarized in Figure 1. These actions have implications for several features of muscle contractions, such as force amplitude, velocity of contraction and relaxation, and impairments that can contribute to fatigue. The purpose of the review is to discuss the influence of the SNS on muscle function and some of the consequences for the neural activation of muscle.
EPINEPHRINE, NOREPINEPHRINE, AND ADRENERGIC RECEPTORS
Activation of the SNS mainly results in the targeted release of norepinephrine (NE) from nerve terminals as well as hormonal release of epinephrine (EPI) from the adrenal medulla. The relative contributions of the neural and hormonal components, which can be estimated from the plasma concentrations of the two catecholamines (9), depends on the context and type of stimulus (20). The plasma concentration of both catecholamines increases during exercise up to 20-fold depending on the magnitude and duration of the effort (30). This increase is even greater in trained individuals ("sport adrenal medulla"; ) and can be augmented by emotional factors. For instance, the basal (preexercise) catecholamine concentration increases before exercise during mental preparation for the activity (30). Interestingly, this mental-autonomic preparation is advantageous for the subsequent motor performance, thus representing an anticipatory (feed-forward) adaptation of the body to the ensuing motor challenge (7).
Epinephrine and NE can bind to the same (adrenergic) receptors (AR) but with different affinity for the different types (α1, α2, and β) and subtypes (10). For instance, EPI and NE have similar affinity for the cardiac β1 AR, whereas EPI has greater affinity than NE for β2 ARs. Besides mediating vasodilation in skeletal muscles, β2 ARs mediate most adrenergic actions on the skeletal muscle fibers. Most of the sympathetic actions described in the following are therefore under the control of circulating EPI. Moreover, β2 ARs can be pharmacologically targeted by specific AR agonists and blockers; β2 ARs are localized with greater density on the sarcolemma of Type-I rather than Type-II muscle fibers and may undergo down-regulation after long-term β2-agonist administration.
MODULATION OF GLUCOSE AND PROTEIN METABOLISM
The SNS plays a role in controlling the storage and availability of energy substrates by coordinating the activity of liver, pancreas, adipose tissue, and skeletal muscle. In skeletal muscle cells, EPI promotes the breakdown of glycogen stores (glycogenolysis) via β2 ARs and inhibits glycogen synthesis, in antagonism with insulin; these actions contribute to the EPI-induced rise in glycemia. However, these mechanisms are profoundly influenced by concurrent contractile activity and are not yet fully understood (18).
Epinephrine also modulates protein metabolism in skeletal muscles by inhibiting proteolytic processes with slow dynamics, as shown in animals and humans when they are subjected to repeated administration of β2-agonists. The anabolic effect appears within 2 d but is attenuated after 14 d of continuous exposure, likely because of receptor down-regulation (24). The long-lasting β2-agonist clenbuterol is listed among the nonsteroidal anabolic drugs prohibited by the World Anti-Doping Agency.
ENHANCEMENT OF THE SODIUM/POTASSIUM PUMP
Skeletal muscle fibers loose potassium into the extracellular fluid during a muscle contraction due to the inability of the sodium/potassium (Na+/K+) pump to counteract the ionic flow across the membrane during the propagation of action potentials. The consequent increase in extracellular potassium concentration depresses cell excitability and may be responsible for excitation failure of muscle fibers during intense exercise (8). Epinephrine potentiates the activity of the Na+/K+ pump, thus potentially attenuating the development of muscle fatigue. A reduced rate of fatigue was indeed observed in electrically stimulated muscles after IV injection of exogenous EPI or after electrically stimulating the release of endogenous EPI (Orbeli effect) in animal models. Similarly, in vitro studies showed that β2-agonists can partly restore action potential amplitude and twitch force of isolated muscle fibers immersed in a bath with increased K+ and lowered Na+ concentrations, simulating the change in ionic gradients during muscle contractions (19).
Despite the evidence from in vitro studies, the administration of β-blockers has not limited the loss of K+ from working muscle fibers in vivo (12). Muscle activity may maximally stimulate the Na+/K+ pump in working muscles, which would reduce the possibility of potentiation by EPI. Nevertheless, circulating EPI still effectively stimulates the activity of the pump in nonworking muscles, thereby attenuating the rise in plasma K+ concentration.
ENHANCEMENT OF ACETYLCHOLINE RELEASE
The loss in excitability associated with intense or long-lasting activity may also be counteracted by the potentiation of neuromuscular propagation. Catecholamines act presynaptically at the motor end plate via both α and β ARs to synchronize vesicle exocytosis and augment the release of neurotransmitter. This action is negligible in resting conditions because of the high safety margin at the nerve-muscle synapse. However, the effect has been observed in animal models when neuromuscular propagation was impaired by partial curarization and restored by administration of catecholamines ("anti-curare effect") (2).
MODULATORY ACTION ON CALCIUM RELEASE AND REUPTAKE
Epinephrine can influence the contractility of skeletal muscle fibers; a comprehensive review of experiments conducted up until the 1980s on animal models is provided by Bowman (2). More recent in vitro studies (11) have revealed that the sympathetic modulation of contractility is mediated by β2 ARs acting in two different ways: i) by acting on ryanodine receptors to facilitate Ca2+ outflow from the sarcoplasmic reticulum (SR); and ii) by acting on phospholamban, an inhibitory protein of Ca2+ pumps, to increase the speed of Ca2+ reuptake in the SR. The first mechanism potentiates twitch force (positive inotropism). The second mechanism increases relaxation rate (positive lusitropy - a term borrowed from the heart physiology), which shortens twitch duration and possibly decreases the amplitude of the single-fiber twitch force and hence reduces the strength of the muscle contraction (Fig. 2). Both fiber types exhibit the inotropic mechanism, whereas the positive lusitropic effect occurs only in Type I fibers as Type II fibers lack phospholamban. The positive inotropic effect, however, can be evoked only with high concentrations of EPI, which casts doubt on its physiological relevance. Conversely, the increase in relaxation rate can be observed in Type I fibers at physiological EPI concentrations as well as in response to electrically stimulated release from the adrenal medulla (2).
Despite the extensive literature on animal models (2), there is little evidence on whether physiological activation of the SNS influences muscle function in humans. Recent findings (22) indicate that activation of the SNS by the cold pressor test (CPT) decreases the half-relaxation time of twitch force (positive lusitropy) in low-threshold (presumably Type I muscle fibers) motor units of the tibialis anterior muscle during a low-force voluntary contraction (Fig. 3). In this experimental series, the subjects maintained constant the discharge rate of a target motor unit of the tibialis anterior muscle during an isometric ankle dorsiflexion. The twitch torque of the target unit could be estimated during the CPT by averaging the joint torque using the discharge times of the action potentials as trigger (22). In a second set of measures of the same study, the subjects maintained the joint torque constant at 10% of the maximal torque; in these conditions, the motor unit discharge rate increased during the CPT as compared with baseline, which suggested an increase in the neural drive to muscle to compensate for the reduced fusion of twitch forces (22). The decrease in twitch fusion due to briefer twitch durations should also increase the fluctuations in force, which has been observed when individuals are stressed (3) and in asthmatic subjects treated with β2-agonists (28).
The results we obtained (22) during voluntary contractions were partly confirmed during electrically elicited contractions of the tibialis anterior muscle that showed a decrease in the amplitude of the twitch force during a CPT, although the lusitropic effect was not observed in these conditions (23). Furthermore, effects similar to those described in Figure 3 were observed on the twitch torque of low-threshold motor units of the tibialis anterior muscle after injection of hypertonic saline that determines muscle pain, a condition in which the SNS is known to be activated (6).
A sympathetically induced positive inotropic effect in skeletal muscles would be appropriate in a fight-or-flight reaction (29). However, there is currently no evidence, in either human or animal models, to indicate that physiological activation of the SNS can evoke a positive inotropic effect. In contrast, a positive lusitropic effect can be elicited in Type I fibers with physiological activation. Although the expression of a positive lusitropic effect, which produces muscle weakening, seems paradoxical during a fight-or-flight reaction, there are potential explanations. First, the reduction in twitch fusion and decrease in muscle force only occurs during submaximal contractions. Conversely, it does not occur when the drive to the muscle increases sufficiently, and some evidence indicates that the input-output gain of the motor neurons can increase under conditions of stress (13). Second, the increase in relaxation rate of low-threshold motor units determines a faster rate of relaxation of the muscle after a contraction. This adjustment is consistent with the generation of cyclic movements at high rates, as required in fights and in flights. This effect probably has similar consequences as the positive lusitropic effect that catecholamines exert on the heart muscle: shortening the duration of the systole to allow for higher heart rates to be attained.
According to this view, the action of EPI is appropriate when there is the need to perform fast alternating movements. However, this action may be counterproductive when a low-force contraction needs to be maintained over time, for instance, during sedentary work activity under conditions of stress. In this case, EPI would weaken the slow-twitch fibers recruited for the light work, thus requiring an adjustment of the motor drive toward higher levels, with increased sense of effort and metabolic cost. In addition, oscillations in muscle force may develop, requiring further adjustment in the motor strategy, such as an increase in the coactivation of antagonist muscles to recover joint stability. These adjustments would be disadvantageous in terms of metabolic cost and fatigue. This and other mechanisms have been hypothesized to link SNS activity with the impairment of muscle function in relation to the pathophysiological mechanism in the development and maintenance of musculoskeletal disorders (21).
BETA AGONISTS AND ANTAGONISTS IN SPORTS
Given the supportive action of the SNS on motor function, an ergogenic effect by sympathomimetics has long been sought within the sport sciences (5). Possible benefits may arise from actions on different systems, such as cardiovascular, respiratory, and musculoskeletal. As previously discussed, most actions at the skeletal muscle level are mediated by β2-ARs that may be selectively targeted by β2-agonists, such as clenbuterol, terbutaline, and salbutamol. These substances are used by asthmatic patients because of the immediate impact on bronchodilatory action with only minimal cardiovascular effects. However, the most frequently reported consequence for the motor system is the occurrence of tremor (28). This effect is often attributed to a decrease in twitch fusion in submaximal contractions as produced by the positive lusitropic effect, although an effect mediated by muscle spindles has also been postulated (References in (2)). Accordingly, β-blockers such as propranolol (unselective, β1-β2), which have a negative lusitropic effect and delay the relaxation of force twitch (1), are commonly used as a treatment for essential tremor. For this reason, these substances are prohibited by the World Anti-Doping Agency in competitions such as archery and shooting.
There is little evidence of an ergogenic effect by inhaled β2-agonists in athletes. Seventeen of 19 randomized placebo-controlled studies failed to find any improvement in endurance performance, such as during cycling, long-distance running, and cross-country skiing (14). More consistent evidence was instead provided by studies in which oral administration of the drugs was tested (4,16,27); this modality produces a higher plasma concentration of the drug as compared with inhalation. Moreover, many studies reported larger effects of β2-agonists in short-explosive tasks, such as the Wingate test (4,16,26), than in endurance tasks (27). It is likely that when the EPI concentration rises, as during progressive endurance tasks, the administered β2-agonist competes with EPI and, being in general less effective than EPI (so-called partial agonist), may act as an antagonist (17).
Although all studies agree that improved performance because of β2-agonists cannot be solely attributed to improvement in respiratory function, it is uncertain whether the main action is a positive inotropic effect on the skeletal muscle fibers or other factors that influence blood circulation, availability of energy substrates, or potassium homeostasis. All β2-agonists are prohibited by the World Anti-Doping Agency, although a therapeutic use exemption is accepted for those administered by inhalation.
Repetitive administration of β2-agonists (e.g., clenbuterol) is practiced by those who want to increase muscle mass by exploiting its anabolic effect (24). Short- and long-term administration of β2-agonists generally increases muscle force, although there may also be a down-regulation of β2-ARs and a decrease in treatment efficacy.
The SNS exerts multiple effects at the muscle level mainly through the action of EPI on β2-ARs located on the skeletal muscle fiber. These actions support intense motor activity and, together with the effects of the SNS on other organ systems, are appropriate for a fight-or-flight response. However, they cannot always be classified as ergogenic, as in the case of the lusitropic effect on Type I fibers.
Most of the knowledge on these mechanisms is based on animal and in vitro studies, and their functional relevance in humans is less well understood. The main challenge in furthering our understanding of these mechanisms in humans in vivo is to disentangle the specific action at the muscle level from the concomitant and widespread actions that catecholamines mediate throughout the body.
Part of this work was supported by grants from Regione Piemonte, Ricerca Sanitaria Finalizzata (2007, 2008) (S.R.) and by the European Project TREMOR (Contract 224051) (D.F.).
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