European Journal of Applied Physiology

https://doi.org/10.1007/s00421-021-04756-8

INVITED REVIEW

Muscle metaboreflex adaptations to exercise training in health

and disease
Gabriel Gama1,2 · Paulo Farinatti1,2,3 · Marcus Vinicius dos Santos Rangel1,2 · Pedro Augusto
de Carvalho Mira4,5 · Mateus Camaroti Laterza5 · Antonio Crisafulli6 · Juliana Pereira Borges1,2

Received: 29 April 2021 / Accepted: 19 June 2021

© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021

Abstract
Abnormalities in the muscle metaboreflex concur to exercise intolerance and greater cardiovascular risk. Exercise training
benefits neurocardiovascular function at rest and during exercise, but its role in favoring muscle metaboreflex in health and
disease remains controversial. While some authors demonstrated that exercise training enhanced the sensitization of muscle
metabolically afferents and improved neurocardiovascular responses to muscle metaboreflex activation, others reported unal-
tered responses. This narrative review aimed to: (a) highlight the current evidence on the effects of exercise training upon
cardiovascular and autonomic responses to muscle metaboreflex activation; (b) analyze the role of training components and
indicate potential mechanisms of metaboreflex adaptations; and (c) address key methodological features for future research.
Though limited, accumulated evidence suggests that muscle metaboreflex adaptations depend on the individual clinical status,
exercise modality, and training duration. In healthy populations, most trials negated the hypothesis of metaboreflex improve-
ment due to chronic exercise, irrespective of the training duration. Favorable changes in patients with impaired metaboreflex,
particularly chronic heart failure, mostly resulted from long-term interventions (> 16 weeks) including aerobic exercise of
moderate to high intensity, performed in isolation or within multimodal training. Potential mechanisms of metaboreflex
improvements include enhanced sensitivity of channels and receptors, greater antioxidant capacity, lower metabolite accumu-
lation, increased functional sympatholysis, and muscle perfusion. Future research should investigate: (1) the dose–response
relationship of training components within different exercise modalities to elicit improvements in individuals showing intact
or impaired muscle metaboreflex; and (2) potential and specific underlying mechanisms of metaboreflex improvements in
individuals with different medical conditions.

Keywords Exercise pressor reflex · Blood pressure · Muscle sympathetic nerve activity · Cardiovascular physiology ·
Health

Abbreviations CAT​ Catalase

ASICs Acid-sensing ion channels CB1 Cannabinoid receptor type-1
BFR Blood flow restriction CHF Chronic heart failure
COX-2 Cyclooxygenase-2
eNOS Nitric oxide synthase
Communicated by Michael Lindinger .

4
* Juliana Pereira Borges Laboratory of Exercise Sciences, Department of Physiology
julipborges@gmail.com and Pharmacology, Fluminense Federal University, Niteroi,
RJ, Brazil
1
Laboratory of Physical Activity and Health Promotion, 5
Cardiovascular Research Unit and Exercise Physiology
Institute of Physical Education and Sports, University of Rio
‑ InCFEx, University Hospital and Faculty of Physical
de Janeiro State, Rua São Francisco Xavier, 524, sala 8133F,
Education and Sports, Federal University of Juiz de Fora,
Maracanã, Rio de Janeiro, RJ, CEP 20550‑013, Brazil
Juiz de Fora, MG, Brazil
2
Graduate Program in Exercise and Sports Sciences, 6
Department of Medical Science and Public Health,
University of Rio de Janeiro State, Rio de Janeiro, RJ, Brazil
University of Cagliari, Cagliari, Italy
3
Graduate Program in Physical Activity Sciences, Salgado de
Oliveira University, Niteroi, RJ, Brazil

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 European Journal of Applied Physiology

EPR Exercise pressor reflex hypertension, diabetes, obesity, spinal cord injury, multiple
ExT Exercise training sclerosis, hepatic cirrhosis, or HIV infection (Crisafulli et al.
FITT Frequency, intensity time and type 2009, 2007; Delaney et al. 2010; Dipla et al. 2010; Holwerda
MAP Mean arterial pressure et al. 2016; Marongiu et al. 2015; Roberto et al. 2012; Gama
MSNA Muscle sympathetic nervous activity et al. 2021; Mira et al. 2021).
MVC Maximal voluntary contraction It is well known that neural and cardiovascular functions
NO Nitric oxide benefit from physical training, with improvements in auto-
NR Not reported nomic control and blood pressure at rest and during exer-
OSA Obstructive sleep apnea cise (Carter and Ray 2015; Nystoriak and Bhatnagar 2018).
P2 Purinergic receptors Despite this, the role of chronic exercise in improving car-
PECA Post-exercise circulatory arrest diovascular responses mediated by the muscle metaboreflex
SBP Systolic blood pressure remains controversial across different populations (Milia et al.
SHR Spontaneously hypertensive rats 2014; Guerra et al. 2019; Antunes-Correa et al. 2014). Some
SOD Superoxide dismutase trials have demonstrated that treadmill training may enhance
TRPv1 Transient receptor potential vanilloid type-1 the sensitization of impaired metabolically sensitive afferents,
VO 2 Oxygen uptake which contributes to restoring an existing over-activation of
WKY Wistar-Kyoto EPR in humans (Antunes-Correa et al. 2014) or rats (Wang
et al. 2012, 2010b), while others failed to show improvements
in cardiovascular and autonomic responses to metaboreflex
Introduction activation in healthy individuals or patients with multiple
sclerosis (Ray and Carrasco 2000; Magnani et al. 2016).
In 1937, Alam & Smirk first described the existence of a Several factors help to explain those mixed findings, such as
blood pressure raising reflex emerging from the skeletal the subjects’ clinical condition, and strategies to activate the
muscles in response to physical exercise, termed as muscle metaboreflex. Additionally, dissimilarities in exercise training
metaboreflex. Afferent stimuli from muscle metabo- and protocols (e.g., long vs. short duration; aerobic vs. resistance
mechano-reflex mediate the exercise pressor reflex [EPR] exercises) may concur with different metaboreflex adaptations,
(or ergoreflex), acknowledged as one of the several neu- as the magnitude of EPR is acknowledged to be proportional
ral mechanisms (e.g. central command, baroreflex, carotid to the amount of exercised muscle mass (Chen and Bonham
chemoreflex, and cardiopulmonary baroreceptors) influenc- 2010; Estrada et al. 2020), and to exercise type and intensity
ing the autonomic nervous system control of cardiovascu- (Victor and Seals 1989).
lar adjustments to attend the demands of working muscles A review of experimental trials investigating the muscle
(Fisher et al. 2015). metaboreflex adaptations to chronic exercise would be useful
During physical effort, the activation of muscle metabore- for a better understanding of the strengths and weaknesses of
flex enhances the sympathetic nervous activity, increasing the current research. This narrative review aimed to highlight
cardiac output, systemic vascular resistance, and mean arte- the accumulated evidence regarding the effects of exercise
rial pressure [MAP] (Crisafulli et al. 2003; Boushel 2010; training upon cardiovascular and autonomic responses medi-
Michelini et al. 2015). The muscle metaboreflex is primarily ated by muscle metaboreflex. Besides discussing the effects
activated by chemically sensitive group IV afferent nerve end- of chronic exercise on the metaboreflex in health and disease,
ings, which are stimulated by metabolites produced by exercis- the influence of methodological features has been analyzed,
ing muscles, such as lactic acid, potassium, bradykinin, ara- as the strategies to activate the metaboreflex and role of train-
chidonic acid products, adenosine triphosphate, deprotonated ing components. In addition, potential mechanisms underlying
phosphate/adenosine, and low-intramuscular pH (Kaufman favorable metaboreflex adaptations to chronic exercise have
et al. 2002; Mark et al. 1985). If group IV muscle afferent been suggested.
feedback is blunted or pharmacologically blocked, the increase
in MAP may not be enough to assure appropriate muscle blood
flow and oxygen supply, leading to premature fatigue and Search strategy and results
exercise intolerance (Amann et al. 2015, 2020). On the other
hand, an exaggerated EPR has been associated with increased A structured search included articles up to April 2021,
sympathetic-induced vasoconstriction in the vasculature of published in English. The electronic databases PubMed,
exercising muscles and higher cardiovascular risk during or Web of Science, and Scopus were consulted. Boolean
after physical activity (Prodel et al. 2016; Greaney et al. 2015; searches were performed in electronic databases to iden-
Grotle et al. 2020). These abnormal responses are observed in tify relevant studies, using Mesh terms related to “muscle
some chronic conditions, such as chronic heart failure (CHF), metaboreflex” AND “exercise training”. Qualifying trials

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European Journal of Applied Physiology

should primarily investigate the effects of exercise train- et al. 1987). Thus, moderate- to high-intensity isometric
ing on cardiovascular and autonomic responses to mus- exercise protocols should be preferred over mild dynamic
cle metaboreflex in either animals or humans without age exercises when aiming to activate the muscle metabore-
limits, and report at least three of the FITT components flex, since the accumulation of metabolites is more likely
(frequency, intensity, time, and type) of exercise interven- to occur when muscle blood vessels are continuously com-
tions. We excluded review, cross-sectional, and epidemio- pressed (Grotle et al. 2020). Most trials investigating the
logical studies. Of the 4,213 articles initially found, 17 exercise training adaptations to muscle metaboreflex were
were retained. All trials included young adult samples, published before those recent findings (Katayama et al.
except for one trial with older rodents (Caron et al. 2018). 2018; Grotle et al. 2020). This probably explains why all
Table 1 depicts the extracted information, including sam- included studies applied loads lower than 40% of MVC
ple characteristics, FITT components, techniques applied (please, refer to Table 1) to activate the metaboreflex,
for metaboreflex activation, and main findings. The follow- except for one trial in which dynamic handgrip at 50% of
ing sections discuss those features in detail. MVC was performed (Piepoli et al. 1996). This may be
considered as a potential limitation of the current research.
In studies with animals, intra-arterial injection of meta-
bolic (i.e., lactic acid and bradykinin) (Caron et al. 2018)
Techniques to activate the muscle or chemical (i.e., capsaicin) (Wang et al. 2012, 2010b) sub-
metaboreflex stances have been used to activate the muscle metaboreflex.
Capsaicin is an active component of chili peppers targeting
The muscle metaboreflex was in general activated by post- the transient receptor potential vanilloid type-1 (TRPv1)
exercise circulatory arrest (PECA) (Antunes-Correa et al. in group IV afferent neurons, which are sensitive to tem-
2014; Guerra et al. 2019; Somers et al. 1992; Trombetta perature and pH changes—when stimulated, they increase
et al. 2003; Ray and Carrasco 2000; Notarius et al. 2019; efferent MSNA (Teixeira et al. 2020; Wang et al. 2012).
Fisher and White 1999; Saito et al. 2009; Piepoli et al. Although those substances seem to successfully activate the
1996; Magnani et al. 2018; Milia et al. 2014; Crisafulli muscle metaboreflex, its optimal dose is still undefined given
et al. 2018), except in two studies that used a positive- the wide variation among studies (please, refer to Table 1).
pressure chamber (Mostoufi-Moab et al. 1998) or isomet- A recent cross sectional study (Vianna et al. 2018) showed
ric knee extension exercise (Sundblad et al. 2018). While that a topical application of a capsaicin-based analgesic
these two latter strategies make it difficult to distinguish balm in the forearm of humans attenuated the blood pressure
whether changes are due to isolated or simultaneous adap- and MSNA responses evoked by PECA, indicating that the
tations in muscle metaboreflex, mechanoreflex, or central TRPv1 receptors contribute to muscle metaboreflex. How-
command, PECA is a non-invasive and non-pharmacolog- ever, the use of capsaicin-based analgesic balms to assess
ical method widely applied to isolate the metabolic com- the effects of exercise training on muscle metaboreflex in
ponent of EPR, by arresting the blood flow of exercising humans is yet to be determined.
muscles with a supra systolic level cuff occlusion that traps
the metabolic by-products after the exercise termination
(Teixeira et al. 2020; Crisafulli 2017; Boushel 2010). For Exercise training and muscle metaboreflex
this reason, the assessment of cardiovascular and auto- activation in health
nomic responses must be performed after the exercise
cessation, as well as during and not after the circulatory The majority of studies including healthy individuals or
arrest. animals reported unchanged cardiovascular and autonomic
Another important aspect of the muscle metabore- responses during metaboreflex activation after exercise train-
flex activation, is the exercise intensity and whether it is ing (Crisafulli et al. 2018; Fisher and White 1999; Ray and
dynamic or isometric. It has been shown that increases in Carrasco 2000; Saito et al. 2009; Caron et al. 2018). Only
muscle sympathetic nervous activity (MSNA) and MAP three out of eight studies (37.5%) observed favorable adap-
during isometric handgrip depend on the intensity of mus- tations in healthy individuals (Mostoufi-Moab et al. 1998;
cle contraction (Katayama et al. 2018). Isometric handgrip Somers et al. 1992; Sundblad et al. 2018), including lower
at 40% of maximal voluntary contraction (MVC) activates blood pressure and lactate accumulation (Mostoufi-Moab
the muscle metaboreflex and overrides the baroreflex- et al. 1998), decreased sympathetic activity (Somers et al.
mediated inhibition of sympathetic vasomotor outflow 1992), and reductions in heart rate and MAP (Sundblad et al.
(Katayama et al. 2018), whereas, mild dynamic handgrip 2018). However, as above-mentioned Mostoufi-Moab et al.
and arm cycling seem to increase the heart rate and arterial (1998) and Sundblad et al. (2018) assessed the responses to
pressure, but not MSNA (Victor and Seals 1989; Victor metaboreflex activation during exercise instead of during

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 Table 1  Description of studies investigating the effects of exercise training on muscle metaboreflex in health and disease
Study Sample Exercise training (FITT) Metaboreflex activation Main findings

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(Antunes-Correa et al. 2014) CHF Untrained (n = 17); Frequency: 3 days/wk PECA (2 min at 240 mmHg) after iso- Improved MSNA control via metabore-
CHF ExT (n = 17) Intensity: 60–72% ­VO2peak metric leg exercise flex. Increased TRPv1 and CB1 expres-
Time: 50–60 min, 17 wks sion and COX-2 pathway. Reduction in
Type: stretching; cycling; strength skeletal muscle inflammation
training
(Guerra et al. 2019) OSA Untrained (n = 21); Frequency: 3 days/wk PECA (2 min at 240 mmHg) after iso- Increased muscle metaboreflex sensitiv-
OSA ExT (n = 20) Intensity: anaerobic threshold metric handgrip ity and muscle blood flow, potentially
Time: 50–60 min, 24 wks contributing for increased exercise
Type: stretching; cycling; strength performance
training
(Magnani et al. 2016) Multiple sclerosis: Frequency: 3 days/wk PECA (3 min at 50 mmHg > SBP) after Hemodynamic dysregulation during
Intervention (n = 11); Intensity: cycling 50–80% V ­ O2max; dynamic handgrip metaboreflex activation was not reversed
Controls (n = 10) Strength 1–3 sets of 8–12 reps with by ExT
15–30% of maximum load
Time: 60 min, 26 wks
Type: stretching; cycling; strength
training
(Notarius et al. 2019) CHF (n = 27); Frequency: 5 days/wk PECA (2 min at 200 mmHg) after iso- Lowered sympathetic outflow within
Healthy controls (n = 18) Intensity: 60–70% ­VO2peak metric handgrip metaboreflex activation, with reduced
Time: 15–60 min, 26 wks MSNA at rest and during mild cycling
Type: walking; strength training
(Trombetta et al. 2003) Obese women: Frequency: 3 days/wk PECA (2 min at 240 mmHg) after iso- Weight loss improved muscle metabore-
Hypocaloric diet (n = 24); Intensity: ≤ 10% resp. comp. point metric handgrip flex control
Hypocaloric diet + ExT (n = 25); Time: 60 min, 16 wks
Nonadherent (n = 10) Type: stretching; cycling; strength
training
(Milia et al. 2014) Spinal cord injured (n = 9) Frequency: 3–5 h/wk PECA (3 min at 50 mmHg > SBP) after Improved hemodynamic response to
Intensity: 60% maximal workload arm cranking muscle metaboreflex activation
Time: NR, 52 wks
Type: arm cranking
(Piepoli et al. 1996) CHF (n = 12); Frequency: 2–3 days/wk PECA (3 min at 30 mmHg > SBP) after Reduced EPR in CHF vs. controls
Healthy controls (n = 10) Intensity: 40 contractions/min at 100% dynamic handgrip
MVC (dynamic)
Time: 15 min, 6 wks
Type: unilateral isometric and dynamic
handgrip
(Fisher and White 1999) Healthy active (n = 17) Frequency: 3 days/wk PECA (2 min at 200 mmHg) after heel Attenuation of blood pressure and heart
Intensity: 4 × 30 reps/min with raise with BFR rate in the untrained limb during
load ≤ 10% body mass exercise, but not in isolated muscle
Time: 6 min, 6 wks metaboreflex
Type: unilateral heel raise
European Journal of Applied Physiology
 Table 1  (continued)
Study Sample Exercise training (FITT) Metaboreflex activation Main findings

(Saito et al. 2009) Healthy active: Frequency: 4 days/wk PECA (2 min) after isometric or Increased MSNA due to central neural
ExT (n = 18); Intensity: 3 × 10 of 10 s (100% MVC) dynamic handgrip (occlusion level factors rather than to muscle metabore-
Controls (n = 18) Time: NR, 4 wks NR) flex
Type: unilateral isometric handgrip
(Ray and Carrasco 2000) Healthy: Frequency: 4 days/wk PECA (2 min at 220 mmHg) after iso- Lowered resting blood pressure, without
ExT (n = 9); Intensity: 30% MVC metric handgrip changes in MSNA and cardiovascu-
Sham-ExT (n = 7); Time: 27 min, 5 wks lar responses to muscle metaboreflex
Controls (n = 8) Type: unilateral isometric handgrip activation
European Journal of Applied Physiology

(Mostoufi-Moab et al. 1998) Healthy (n = 10) Frequency: 5 days/wk Dynamic handgrip in a pressurized Higher positive-pressure threshold for
Intensity: 12 contractions/min at Plexiglas tank metaboreceptor activation, with lower
30–35% MVC metabolite concentration and MAP dur-
Time: 30 min, 4 wks ing ischemic exercise
Type: unilateral dynamic handgrip
(Somers et al. 1992) Healthy males (n = 8) Frequency: 5 days/wk PECA (2 min above SBP) after isomet- Attenuated sympathetic activity and
Intensity: 2 × 30% MVC until fatigue ric handgrip unchanged cardiovascular responses to
Time: NR, 6 wks muscle metaboreflex activation
Type: unilateral dynamic handgrip
(Crisafulli et al. 2018) Healthy active males (n = 17) Frequency: 3 days/wk PECA (3 min at 50 mmHg > SBP) after Decreased MAP during exercise was not
Intensity: 30 contractions/min at 30% dynamic handgrip related to metaboreflex activity
MVC with BFR (75–150% of resting
SBP)
Time: 6 min, 4 wks
Type: unilateral dynamic handgrip with
BFR
(Sundblad et al. 2018) Healthy active males (n = 10) Frequency: 4 days/wk Isometric unilateral knee extension Reduced EPR due to peripheral metabolic
Intensity: highest tolerable workload changes during relative ischemia
Time: 45 min, 5 wks
Type: right or left dynamic unilateral
knee-extension
(Caron et al. 2018) Sprague–Dawley rats: Frequency: 3 days/wk Lactic acid injections (0.5, 1, 2, and Age-related decrease in metabosensitive
3 months (n = 12); Intensity: 13.5 to 18 m/min 3 mM/0.1 ml) afferent responses to chemical stimuli
6 months (n = 12); Time: 10–60 min, 8 wks was not restored by ExT
12 months (n = 12); Type: treadmill running
20 months (n = 12);
12 months ExT (n = 10);
20 months ExT (n = 11)
(Wang et al. 2012) Sprague–Dawley rats: Frequency: 5 days/wk Capsaicin injections (0.2 or Improved sensitization of muscle afferents
Sedentary (n = 42); Intensity: 10–25 m/min (0–10% grade) 2.0 μg/0.15 ml) partially due to restoring dysfunctions
Sham ExT (n = 40); Time: 10–60 min, 7 wks of P2X and TRPV1 receptors
CHF sedentary (n = 42); Type: treadmill running
CHF ExT (n = 43)

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 European Journal of Applied Physiology

PECA, which makes it difficult to isolate the contribution of

Lowered blood pressure and sympathetic

metabolic component from mechanical stimuli and the cen-
tral command in these responses. Ultimately, a single trial
outflow following EPR activation provided specific data of improved muscle metaboreflex,
after 6-week training with handgrip in a very small sam-
ple of five healthy individuals (Somers et al. 1992): similar
cardiovascular responses during PECA occurred in parallel
with attenuated sympathetic activation vs. pre-training.
It is worth noticing that except for a trial, including rats
Main findings

(Caron et al. 2018), all previous research with healthy indi-

viduals applied resistance training protocols involving small
muscle mass (handgrip or heel raise exercise), and relatively
short duration (up to 6 weeks) (Ray and Carrasco 2000;
Crisafulli et al. 2018; Fisher and White 1999; Saito et al.
Capsaicin injections (0.1 or 1.0 μg/kg,

2009; Mostoufi-Moab et al. 1998; Somers et al. 1992; Sund-

blad et al. 2018). Considering that the magnitude of EPR
is acknowledged to be proportional to the amount of exer-
Metaboreflex activation

cised muscle mass (Chen and Bonham 2010; Estrada et al.

2020), those features may have concurred with the lack of
metaboreflex adaptations. Exercise training limited to small
muscles may be insufficient to produce overall metabore-
0.2 ml)

flex adaptations, especially in individuals with moderate- to

high physical fitness, who may need full-body exercises and
more severe exercise regimens for this purpose. In short,
the accumulated evidence only supports the premise that
Intensity: 10–25 m/min (0–10% grade)

exercise training performed with small muscle mass and

short duration is not capable of improving an intact muscle
metaboreflex. This is not sufficient to determine whether an
intact metaboreflex might be improved by exercise training
Exercise training (FITT)

Time: 10–60 min, 7 wks

Type: treadmill running

or if there is a “ceiling” effect for metaboreflex function

Frequency: 5 days/wk

under these circumstances. Further studies investigating

exercise interventions with different modalities (e.g., aer-
obic vs. dynamic/isometric resistance training), exercised
muscle mass (e.g., small vs. large), and training duration
(e.g., short vs. long) are warranted to dismiss whether the
metaboreflex in healthy individuals might be influenced by
chronic exercise.
CHF sedentary (n = 13);
Sprague–Dawley rats:

Exercise training and muscle metaboreflex

Sham ExT (n = 13);
Sedentary (n = 13);

CHF ExT (n = 13)

activation in disease

Chronic heart failure

Sample

The extent to which the CHF impairs the muscle metabore-

flex is uncertain since prior studies have reported exag-
gerated (Notarius et al. 2001, 2019; Piepoli et al. 1996) or
blunted metaboreflex control of MSNA (Sterns et al. 1991;
Table 1  (continued)

(Wang et al. 2010b)

Middlekauff et al. 2000; Negrao et al. 2001a). However,

in both cases an over-activation of EPR and MSNA dur-
ing exercise seems to result from mechano- and metabore-
flex abnormalities (Middlekauff and Sinoway 2007; Smith
Study

et al. 2005a). Besides, it is consensual that cardiovascular

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European Journal of Applied Physiology

responses to muscle metaboreflex are altered in CHF Other chronic conditions

(Angius and Crisafulli 2020). Typically, increases in MAP
due to muscle metaboreflex activation primarily result from Our review allows thinking that despite the potential effects
greater cardiac output (Spranger et al. 2013). However, given of exercise training on the muscle metaboreflex in several
their limited ability to enhance inotropism (O’Leary et al. diseases, this issue has been poorly explored by the current
2004), patients with CHF exhibit a functional shift from a research. Besides CHF, the metaboreflex adaptations in other
flow-mediated (i.e., cardiac output-increase) to a vasocon- cardiometabolic diseases were investigated only by a single
striction-mediated mechanism (Angius and Crisafulli 2020; trial including individuals with obesity (Trombetta et al.
Crisafulli 2017; O’Leary et al. 2019; Barrett-O’Keefe et al. 2003). The muscle metaboreflex control is often lowered in
2018). The greater sympathetic-induced vasoconstriction obesity (Negrao et al. 2001b). The greater MSNA usually
restricts the blood flow to exercising muscles, reducing the observed in these individuals (Negrao et al. 2001b) seems to
muscle perfusion and preventing an appropriate metabolite be mediated by baroreflex dysfunction rather than by muscle
clearance during exercise—in consequence, the exercise metaboreflex (Lee et al. 2020; Negrao et al. 2001b). Interest-
tolerance in patients with CHF is typically compromised ingly, weight loss induced by hypocaloric diet associated or
(Amann et al. 2015; Angius and Crisafulli 2020). not with multimodal exercise has been reported to increase
We found five trials investigating the effects of chronic MSNA levels during PECA (Trombetta et al. 2003). Despite
exercise on the muscle metaboreflex in patients with CHF, this, the isolated effect of exercise training on the muscle
which reported divergent findings (Antunes-Correa et al. metaboreflex of individuals with obesity has not been so far
2014; Piepoli et al. 1996; Notarius et al. 2019; Wang et al. investigated.
2012, 2010b). The early study by Piepoli et al. (1996) dem- Several other cardiometabolic diseases have been associ-
onstrated that handgrip-trained patients reduced their sys- ated with abnormalities in the muscle metaboreflex, such
tolic and diastolic blood pressure, as well as leg vascular as type I and II diabetes mellitus (Holwerda et al. 2016;
resistance in response to PECA. Investigations by Wang Roberto et al. 2012; Grotle et al. 2021), coronary artery dis-
et al. (2012; 2010b) applied 5 to 7 weeks of treadmill run- ease (Magnani et al. 2018), metabolic syndrome (Doneddu
ning interventions to rats with CHF and blunted metabore- et al. 2020; Milia et al. 2015), and hypertension (Grotle et al.
flex, observing a partial metaboreflex restoration reflected by 2020). We could not find studies investigating the influence
increased discharge of group IV afferents, MAP, and heart of chronic exercise on the metaboreflex of patients with
rate following capsaicin injection. These findings were later those conditions, with the exception of a single trial includ-
confirmed in a trial with humans (Antunes-Correa et al. ing spontaneously hypertensive rats (Mizuno et al. 2015),
2014), reporting increased MSNA via muscle metaboreflex which applied voluntary wheel running and therefore did
after multimodal training. Restoration of the expression of not provide sufficient information on FITT components. It
TRPv1, and purinergic 2X (P2X) receptors—usually down- is accepted that patients with high blood pressure exhibit
and up-regulated in CHF, respectively, (Wang et al. 2010a; increased EPR-mediated sympathetic and cardiovascular
Smith et al. 2005b)—were observed after training in experi- responses to acute exercise (Grotle et al. 2020). This seems
ments with both humans and animals (Antunes-Correa et al. to be partially counteracted by attenuating muscle afferent
2014; Wang et al. 2012). discharge through intrathecal injection of fentanyl in humans
On the other hand, data from Notarius et al. (2019) (Sidhu et al. 2019) or antagonizing TRPv1 muscle recep-
disagreed with the premise that a blunted metaboreflex in tors in rats (Mizuno et al. 2011). In that single experiment
patients with CHF could be counteracted by exercise train- addressing the metaboreflex responses to voluntary exercise
ing. Those authors showed that a 6-month cardiac reha- in spontaneously hypertensive rats, three months of volun-
bilitation program decreased the MSNA during muscle tary wheel running reduced the increases in MAP and renal
metaboreflex activation, without changes in the blood pres- sympathetic activity induced by capsaicin, passive stretch,
sure in individuals with reduced ejection fraction. It has been and static contractions (Mizuno et al. 2015). This is sugges-
claimed that factors as the disease severity, particularities tive that regular exercise may normalize the dysfunction of
of exercise protocols, and posture during microneurography both mechanically and chemically sensitive components of
assessment might influence the analysis of muscle metabore- EPR in hypertension. Though interesting, this hypothesis
flex. These potential confounding factors, associated with deserves further investigation.
the limited trials including patients with CHF reinforce Considering that evidence on cardiometabolic diseases
the need for additional research to investigate whether the other than CHF are scarce, it would be nonetheless rele-
often impaired muscle metaboreflex in this group might be vant to provide insights into the role of exercise training
improved by exercise training. on restoring EPR-induced hemodynamic and autonomic
responses in different clinical settings, especially when
considering that potential metaboreflex abnormalities may

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 European Journal of Applied Physiology

result from specific and diverse mechanisms. In regards to baseline status, exercise modality, or duration in eliciting
pathological conditions not strictly related to cardiometa- exercise-related benefits in the muscle baroreflex.
bolic diseases, exercise-related improvements in the muscle The range of session durations was greater in resistance
metaboreflex have been found in patients with spinal cord (6–45 min) vs. aerobic or multimodal training (50–60 min).
injury after 52-week arm cranking intervention (Milia et al. Speculations on the role of the duration of aerobic exer-
2014), and obstructive sleep apnea after 24 weeks of multi- cise sessions to produce changes in the metaboreflex are
modal training (Guerra et al. 2019). On the contrary, patients therefore not possible. On the other hand, resistance train-
with multiple sclerosis performing a 6-month multimodal ing performed with sessions of similar duration produced
training intervention did not reverse their blunted stroke either favorable (Mostoufi-Moab et al. 1998) or unfavorable
volume response to metaboreflex activation (Magnani et al. effects (Ray and Carrasco 2000) in healthy individuals. Two
2016). However, since MSNA has not been assessed in those studies applied resistance exercise bouts longer than 30 min,
patients, improvements in sympathetic responses to PECA and elicited significant improvements in cardiovascular and
may have occurred irrespective of hemodynamic changes, as autonomic outcomes to metaboreflex activation (Mostoufi-
observed in other populations (Antunes-Correa et al. 2014; Moab et al. 1998; Sundblad et al. 2018). However, it must be
Guerra et al. 2019). remembered that those trials performed assessments during
exercise and not during PECA, which may be considered as
a major limitation in the analysis of responses to metabore-
flex activation. Unfortunately, the only study that used PECA
FITT components and exercise‑training did not report the duration of the exercise sessions (Somers
adaptations in the muscle metaboreflex et al. 1992). In regards to research including patients with
chronic disease, a single study applied 15 min of dynamic
In the present study, interventions applied exclusive aero- handgrip performed during 6 weeks to individuals with CHF
bic (Caron et al. 2018; Milia et al. 2014; Wang et al. 2012, (Piepoli et al. 1996). Improvements in the metaboreflex have
2010b), exclusive resistance (Piepoli et al. 1996; Fisher been reported, reflected by lowered blood pressure and leg
and White 1999; Saito et al. 2009; Ray and Carrasco 2000; vascular resistance in response to PECA.
Mostoufi-Moab et al. 1998; Somers et al. 1992; Crisafulli In aerobic interventions, at least three sessions per week
et al. 2018; Sundblad et al. 2018), or combined (multimodal) performed at moderate intensity (60–80% ­VO2max) seemed
training (Antunes-Correa et al. 2014; Guerra et al. 2019; to be enough to improve cardiovascular and autonomic
Magnani et al. 2016; Notarius et al. 2019; Trombetta et al. responses to muscle metaboreflex activation. However,
2003). On average, exercise training was performed three the small range of exercise frequency and intensity across
days/week (3–5 days/week) for 13 ± 12 weeks (4–52 weeks). studies precludes further assumptions on their relative role.
Aerobic training was of moderate- to high intensity (50–80% Adequate information on the intensity of resistance training
­VO2max, or at anaerobic threshold). Resistance training was lacks in many trials (Antunes-Correa et al. 2014; Trombetta
mostly dynamic (six out of eight trials) and applied loads et al. 2003; Fisher and White 1999). In addition, the large
corresponding to 30 or 100% of MVC or 10% of body mass methodological variation concerning issues as type of con-
(please, refer to Table 1). traction (i.e., isometric, or dynamic), blood flow-restriction,
It would be tempting to state that aerobic training per- or parameters for establishing workloads (i.e., % MVC, %
formed in isolation or within multimodal interventions body mass, and highest tolerable workload) limits the analy-
would be more effective in favoring muscle metaboreflex sis of training intensity as a moderator of adaptations in the
than resistance training alone, as positive outcomes were physiological responses to metaboreflex activation.
found in ~ 80% (seven out of nine) of studies including aero-
bic exercise vs. 50% (four out of eight) of those exclusively
applying resistance exercises. Training duration also seems Mechanisms of exercise‑training
to be a relevant factor to achieve greater benefits in muscle adaptations in the muscle metaboreflex
metaboreflex. Approximately 80% (four out of five) of trials
applying more than 10 weeks of training vs. 58% (seven out Although very little information is available on the potential
of 12) of shorter interventions observed some kind of favora- mechanisms of muscle metaboreflex improvements due to
ble adaptation in autonomic or cardiovascular responses to exercise training, they are acknowledged to be multiple and
metaboreflex activation. However, it must be mentioned that complex and seem to rely on individuals’ medical status
most studies with aerobic or multimodal training investi- (Grotle et al. 2020). In theory, all factors influencing the car-
gated individuals with impaired muscle metaboreflex and diovascular and autonomic responses to metaboreflex [please
applied longer interventions vs. isolated resistance training. refer to (Grotle et al. 2020) for additional reading] may be
Therefore, it is difficult to discriminate the relative role of modulated by chronic exercise. Accordingly, exercise-related

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European Journal of Applied Physiology

Fig. 1  Schematic illustration of the potential mechanisms underly- tors (i.e., ASICs channels, TRPv1, P2 and COX-2 receptors), these
ing exercise-related adaptations in the muscle metaboreflex. Exer- changes restore the sensitization of group IV muscle afferents and
cise training reduces the oxidative stress during acute exercise and muscle metaboreflex control of MSNA MSNA muscle sympathetic
increases the bioavailability of locally released vasodilator sub- nervous activity, SOD superoxide dismutase, CAT​catalase, NO nitric
stances, which enhance the muscle blood flow and reduce the pro- oxide, eNOS nitric oxide synthase, ASICs acid-sensing ion channels,
duction of muscle metabolic by-products during exercise (i.e., lactic TRPv1 transient receptor potential vanilloid type-1, P2 purinergic
acid, potassium, and phosphate ions). Together with training-induced receptors, COX-2 cyclooxygenase-2 receptors.
changes in the expression of muscle metaboreflex-related recep-

improvements may result from a wide spectrum of adapta- reduce the exaggerated locomotor muscle group III/IV affer-
tions, as the sensitivity or expression of channels and recep- ent feedback during exercise in patients with cardiovascular
tors (i.e., ASICs channels, TRPv1, P2 and COX-2 receptors) disease.
(Antunes-Correa et al. 2014; Wang et al. 2012), muscle oxi- Figure 1 presents a schematic illustration of potential
dative stress and antioxidant capacity (de Sousa et al. 2017; mechanisms that could be accounted for metaboreflex adap-
Powers et al. 2016), metabolite accumulation within exercis- tations to chronic exercise, partially based on data from the
ing muscles (McAllister et al. 1996; Deer and Heaps 2013; reviewed studies. As aforementioned, exercise training
Keytsman et al. 2019; Devereux et al. 2012), or functional seems to restore the expression of TRPv1 and P2 receptors
sympatholysis (Mizuno et al. 2014; Jendzjowsky and Delo- in patients with CHF, which is concomitant to improved
rey 2013; Saltin and Mortensen 2012). metaboreflex control of MSNA (Antunes-Correa et al. 2014;
In which specifically concerns the expression of recep- Wang et al. 2012). It is well accepted that reactive oxygen
tors associated with the EPR, studies with animals reported species produced during muscle contraction stimulate group
greater expression of COX-2 and P2, and decreased expres- IV muscle afferents and accentuate the EPR (Grotle et al.
sion of TRPv1 and ASICs vs. controls (Smith et al. 2005b; 2020). This may be attenuated by chronic exercise due to
Wang et al. 2012, 2010a). However, it is unclear whether a greater activity of primary antioxidant enzymes within
those findings translate to humans. A very recent investi- skeletal muscles, particularly as a function of exercise inten-
gation found that TRPv1 and COX-2 protein expression sity and duration (Powers et al. 2016). Muscle metaboreflex
levels were elevated in patients with CHF with reduced is greatly influenced by increases in blood flow to exercis-
ejection fraction compared to healthy individuals, while ing skeletal muscles, as it increases muscle perfusion and
P2 and ASICs were not different between groups (Smith reduces accumulation of metabolic by-products during
et al. 2020). However, to date there have been only minimal exercise (e.g. lactic acid) (Thomas 2015), which might help
studies in humans on this topic, and future studies are war- to attenuate the sensitization of group IV afferents. Skel-
ranted to determine if changes in locomotor muscle TRPv1, etal muscle blood flow is regulated by a complex interac-
P2 and COX-2 expression following exercise training may tion between vasoconstrictor and vasodilator substances,

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 European Journal of Applied Physiology

including nitric oxide (NO), ATP, and prostacyclin (Munch impaired metaboreflex have deficiencies in one or more of
et al. 2018). Increasing the net effect of those vasodilatory those mechanisms, which might help to explain their greater
substances would contribute to exercise hyperemia by induc- responsiveness to exercise training.
ing local vasodilation and overriding sympathetic vasocon- The present state-of-the-art review highlighted issues that
strictor activity during exercise (functional sympatholysis) warrant further research. Key questions to be addressed in
(Munch et al. 2018). Exercise training (in particular aerobic) the future include:
seems to enhance functional sympatholysis by increasing • What would be the optimal dose–response relationship
the release of those vasodilatory substances (Mizuno et al. of training components (FITT) in interventions with differ-
2014; Jendzjowsky and Delorey 2013; Saltin and Mortensen ent exercise modalities, to induce favorable adaptations in
2012) – which adaptation was diminished by NO blockade individuals with intact and impaired muscle metaboreflex?
(Mizuno et al. 2014). Taken together, those vascular adapta- • What would be the characteristics of aerobic, resistance,
tions to exercise training (Ashor et al. 2015) may prevent or or multimodal training to restore the impaired metaboreflex
postpone the critical accumulation of metabolites, therefore, in individuals with chronic pathological conditions, particu-
favoring the muscle metaboreflex. larly cardiometabolic diseases (e.g., CHF, hypertension, dia-
Collectively, these proposed mechanisms are consistent betes, obesity, and coronary artery disease)?
with the hypothesis that individuals with impaired muscle • What would be the mechanisms underlying the poten-
metaboreflex would be more responsive to training adap- tial benefits of exercise training on the muscle metaboreflex
tations than healthy individuals, due to a larger “training in individuals with different medical conditions leading to
window” resulting from the malfunctioning of one or more impaired metaboreflex?
of the mechanisms evoking the metaboreflex (Grotle et al.
2020).
Author contributions GG and JPB: had the idea for the article, GG and
MVSR: performed the literature search and data analysis, GG, PF and
JPB drafted the manuscript, all authors critically revised the manuscript
Conclusions and future directions and approved its submission.

Research on the effects of chronic exercise upon the mus- Funding This work was supported by the National Council for Tech-
cle metaboreflex is scarce. Prior studies with healthy indi- nological and Scientific Development (CNPq, process 303629/2019-3,
recipient PF) and Carlos Chagas Filho Foundation for Research Support
viduals failed to show improvements in cardiovascular and in the State of Rio de Janeiro (FAPERJ, process E-26/110.184/2013,
autonomic responses to metaboreflex activation. However, recipient PF, E-26/202.720/2019, E-26/010.100935/2018 recipient
practically all trials applied short interventions of resistance JPB).
training performed with small muscle mass. The available
evidence is therefore not sufficient to determine whether an Data availability Not applicable.
intact metaboreflex might be improved by exercise training
of different modalities. Declarations
Experiments including patients with chronic diseases
Conflicts of interest The authors declare that the research was con-
often associated with impaired metaboreflex are also limited ducted in the absence of any commercial or financial relationships that
and mixed. However, data from trials with cardiometabolic could be considered a potential conflict of interest.
diseases – particularly CHF – are suggestive that different
modalities of exercise training may improve cardiovascular Ethics approval Not applicable.
and autonomic responses to metaboreflex activation. Favora- Consent to participate Not applicable.
ble adaptations seem to be more likely to occur in response
to long-term aerobic training of moderate- to high intensity, Consent for publication Not applicable.
performed either in isolation or within multimodal routines.
The role of the duration of exercise sessions is yet undefined.
Several mechanisms may be at the origin of muscle
metaboreflex adaptations to chronic exercise, depending References
on the clinical status and modality of exercise (aerobic vs.
resistance, dynamic vs. static etc.). Among the potential Alam M, Smirk FH (1937) Observations in man upon a blood pres-
mechanisms, current research allows suggesting the occur- sure raising reflex arising from the voluntary muscles. J Physiol
rence of adaptations in channels and receptors evoking 89(4):372–383
Amann M, Sidhu SK, Weavil JC, Mangum TS, Venturelli M (2015)
the metaboreflex, greater antioxidant capacity, improved Autonomic responses to exercise: group III/IV muscle afferents
functional sympatholysis, and better muscle perfusion with and fatigue. Auton Neurosci: Basic Clin 188:19–23. https://​doi.​
lower metabolite accumulation. Overall, individuals with org/​10.​1016/j.​autneu.​2014.​10.​018

13
European Journal of Applied Physiology

Amann M, Wan HY, Thurston TS, Georgescu VP, Weavil JC (2020) On de Sousa CV, Sales MM, Rosa TS, Lewis JE, de Andrade RV, Simoes
the influence of group III/IV muscle afferent feedback on endur- HG (2017) The antioxidant effect of exercise: a systematic review
ance exercise performance. Exerc Sport Sci Rev 48(4):209–216. and meta-analysis. Sports Med 47(2):277–293. https://​doi.​org/​10.​
https://​doi.​org/​10.​1249/​JES.​00000​00000​000233 1007/​s40279-​016-​0566-1
Angius L, Crisafulli A (2020) Exercise intolerance and fatigue in Deer RR, Heaps CL (2013) Exercise training enhances multiple mecha-
chronic heart failure: is there a role for group III/IV afferent feed- nisms of relaxation in coronary arteries from ischemic hearts. Am
back? Eur J Prev Cardiol. https://​doi.​org/​10.​1177/​20474​87320​ J Physiol Heart Circ Physiol 305(9):H1321-1331. https://​doi.​org/​
906919 10.​1152/​ajphe​art.​00531.​2013
Antunes-Correa LM, Nobre TS, Groehs RV, Alves MJ, Fernandes T, Delaney EP, Greaney JL, Edwards DG, Rose WC, Fadel PJ, Farquhar
Couto GK, Rondon MU, Oliveira P, Lima M, Mathias W, Brum WB (2010) Exaggerated sympathetic and pressor responses to
PC, Mady C, Almeida DR, Rossoni LV, Oliveira EM, Middle- handgrip exercise in older hypertensive humans: role of the mus-
kauff HR, Negrao CE (2014) Molecular basis for the improvement cle metaboreflex. Am J Physiol Heart Circ Physiol 299(5):H1318-
in muscle metaboreflex and mechanoreflex control in exercise- 1327. https://​doi.​org/​10.​1152/​ajphe​art.​00556.​2010
trained humans with chronic heart failure. Am J Physiol Heart Devereux GR, Coleman D, Wiles JD, Swaine I (2012) Lactate accu-
Circ Physiol 307(11):H1655-1666. https://​doi.​org/​10.​1152/​ajphe​ mulation following isometric exercise training and its relationship
art.​00136.​2014 with reduced resting blood pressure. J Sports Sci 30(11):1141–
Ashor AW, Lara J, Siervo M, Celis-Morales C, Oggioni C, Jakovlje- 1148. https://​doi.​org/​10.​1080/​02640​414.​2012.​692482
vic DG, Mathers JC (2015) Exercise modalities and endothelial Dipla K, Zafeiridis A, Koidou I, Geladas N, Vrabas IS (2010) Altered
function: a systematic review and dose-response meta-analysis of hemodynamic regulation and reflex control during exercise
randomized controlled trials. Sports Med 45(2):279–296. https://​ and recovery in obese boys. Am J Physiol-Heart Circ Physiol
doi.​org/​10.​1007/​s40279-​014-​0272-9 299(6):H2090–H2096
Barrett-O’Keefe Z, Lee JF, Berbert A, Witman MAH, Nativi-Nicolau Doneddu A, Roberto S, Pinna V, Magnani S, Ghiani G, Sainas G,
J, Stehlik J, Richardson RS, Wray DW (2018) Metaboreceptor Mulliri G, Serra S, Kakhak SAH, Milia R, Lecis R, Guicciardi M,
activation in heart failure with reduced ejection fraction: Link- Crisafulli A (2020) Effect of combined mental task and metabore-
ing cardiac and peripheral vascular haemodynamics. Exp Physiol flex activation on hemodynamics and cerebral oxygenation in
103(6):807–818. https://​doi.​org/​10.​1113/​EP086​948 patients with metabolic syndrome. Front Physiol 11:397. https://​
Boushel R (2010) Muscle metaboreflex control of the circulation dur- doi.​org/​10.​3389/​fphys.​2020.​00397
ing exercise. Acta Physiol (oxf) 199(4):367–383. https://​doi.​org/​ Estrada JA, Ducrocq GP, Kaufman MP (2020) The magnitude of the
10.​1111/j.​1748-​1716.​2010.​02133.x exercise pressor reflex is influenced by the active skeletal muscle
Caron G, Decherchi P, Marqueste T (2018) Alteration of metabosensi- mass in the decerebrate rat. Am J Physiol Regul Integr Comp
tive afferent response with aging: exercised versus non-exercised Physiol 318(1):R30–R37. https://​doi.​org/​10.​1152/​ajpre​gu.​00263.​
rats. Front Aging Neurosci 10:367. https://​doi.​org/​10.​3389/​fnagi.​ 2019
2018.​00367 Fisher WJ, White MJ (1999) Training-induced adaptations in the
Carter JR, Ray CA (2015) Sympathetic neural adaptations to exer- central command and peripheral reflex components of the pres-
cise training in humans. Auton Neurosci: Basic Clin 188:36–43. sor response to isometric exercise of the human triceps surae. J
https://​doi.​org/​10.​1016/j.​autneu.​2014.​10.​020 Physiol 520(Pt 2):621–628. https://​doi.​org/​10.​1111/j.​1469-​7793.​
Chen CY, Bonham AC (2010) Postexercise hypotension: central mech- 1999.​00621.x
anisms. Exerc Sport Sci Rev 38(3):122–127. https://​doi.​org/​10.​ Fisher JP, Young CN, Fadel PJ (2015) Autonomic adjustments to exer-
1097/​JES.​0b013​e3181​e372b5 cise in humans. Compr Physiol 5(2):475–512. https://​doi.​org/​10.​
Crisafulli A (2017) The impact of cardiovascular diseases on cardiovas- 1002/​cphy.​c1400​22
cular regulation during exercise in humans: studies on metabore- Gama G, Farinatti P, Crisafulli A, Borges J (2021) Blood pressure
flex activation elicited by the post-exercise muscle ischemia response to muscle metaboreflex activation is impaired in men
method. Curr Cardiol Rev 13(4):293–300. https://d​ oi.o​ rg/1​ 0.2​ 174/​ living with HIV. Int J Sports Med 42(3):246–252. https://​doi.​org/​
15734​03X13​66617​08041​65928 10.​1055/a-​1263-​1124
Crisafulli A, Scott AC, Wensel R, Davos CH, Francis DP, Pagliaro Greaney JL, Wenner MM, Farquhar WB (2015) Exaggerated increases
P, Coats AJ, Concu A, Piepoli MF (2003) Muscle metabore- in blood pressure during isometric muscle contraction in hyper-
flex-induced increases in stroke volume. Med Sci Sports Exerc tension: role for purinergic receptors. Auton Neurosci: Basic Clin
35(2):221–228. https://​doi.​org/​10.​1249/​01.​MSS.​00000​48639.​ 188:51–57. https://​doi.​org/​10.​1016/j.​autneu.​2014.​12.​003
02548.​24 Grotle AK, Macefield VG, Farquhar WB, O’Leary DS, Stone AJ (2020)
Crisafulli A, Salis E, Tocco F, Melis F, Milia R, Pittau G, Caria MA, Recent advances in exercise pressor reflex function in health and
Solinas R, Meloni L, Pagliaro P, Concu A (2007) Impaired central disease. Auton Neurosci: Basic Clin 228:102698. https://​doi.​org/​
hemodynamic response and exaggerated vasoconstriction during 10.​1016/j.​autneu.​2020.​102698
muscle metaboreflex activation in heart failure patients. Am J Grotle AK, Kaur J, Stone AJ, Fadel PJ (2021) Neurovascular dysregula-
Physiol Heart Circ Physiol 292(6):H2988-2996. https://​doi.​org/​ tion during exercise in type 2 diabetes. Front Physiol 12:628840.
10.​1152/​ajphe​art.​00008.​2007 https://​doi.​org/​10.​3389/​fphys.​2021.​628840
Crisafulli A, Milia R, Vitelli S, Caddeo M, Tocco F, Melis F, Concu Guerra RS, Goya TT, Silva RF, Lima MF, Barbosa ERF, Alves M, Rod-
A (2009) Hemodynamic responses to metaboreflex activation: rigues AG, Lorenzi-Filho G, Negrao CE, Ueno-Pardi LM (2019)
insights from spinal cord-injured humans. Eur J Appl Physiol Exercise training increases metaboreflex control in patients with
106(4):525–533. https://​doi.​org/​10.​1007/​s00421-​009-​1045-2 obstructive sleep apnea. Med Sci Sports Exerc 51(3):426–435.
Crisafulli A, de Farias RR, Farinatti P, Lopes KG, Milia R, Sainas G, https://​doi.​org/​10.​1249/​MSS.​00000​00000​001805
Pinna V, Palazzolo G, Doneddu A, Magnani S, Mulliri G, Rob- Holwerda SW, Restaino RM, Manrique C, Lastra G, Fisher JP, Fadel PJ
erto S, Oliveira RB (2018) Blood flow restriction training reduces (2016) Augmented pressor and sympathetic responses to skeletal
blood pressure during exercise without affecting metaboreflex muscle metaboreflex activation in type 2 diabetes patients. Am J
activity. Front Physiol 9:1736. https://​doi.​org/​10.​3389/​fphys.​ Physiol Heart Circ Physiol 310(2):H300-309. https://​doi.​org/​10.​
2018.​01736 1152/​ajphe​art.​00636.​2015

13
 European Journal of Applied Physiology

Jendzjowsky NG, Delorey DS (2013) Short-term exercise training response to metaboreflex activation. Eur J Appl Physiol
enhances functional sympatholysis through a nitric oxide- 115(8):1693–1703. https://​doi.​org/​10.​1007/​s00421-​015-​3153-5
dependent mechanism. J Physiol 591(6):1535–1549. https://​ Mira PAC, Falci MFA, Moreira JB, Guerrero RVD, Ribeiro T, Barbosa
doi.​org/​10.​1113/​jphys​iol.​2012.​238998 K, Pace FHL, Martinez DG, Laterza MC (2021) Blunted blood
Katayama K, Kaur J, Young BE, Barbosa TC, Ogoh S, Fadel PJ pressure response to exercise and isolated muscle metaboreflex
(2018) High-intensity muscle metaboreflex activation attenuates activation in patients with cirrhosis. Appl Physiol Nutr Metabol
cardiopulmonary baroreflex-mediated inhibition of muscle sym- 46(3):273–279. https://​doi.​org/​10.​1139/​apnm-​2020-​0407
pathetic nerve activity. J Appl Physiol 125(3):812–819. https://​ Mizuno M, Murphy MN, Mitchell JH, Smith SA (2011) Antagonism
doi.​org/​10.​1152/​jappl​physi​ol.​00161.​2018 of the TRPv1 receptor partially corrects muscle metaboreflex
Kaufman MP, Hayes SG, Adreani CM, Pickar JG (2002) Discharge overactivity in spontaneously hypertensive rats. J Physiol 589(Pt
properties of group III and IV muscle afferents. Sensorimotor 24):6191–6204. https://​doi.​org/​10.​1113/​jphys​iol.​2011.​214429
control of movement and posture. Springer, Boston, pp 25–32 Mizuno M, Iwamoto GA, Vongpatanasin W, Mitchell JH, Smith SA
Keytsman C, Hansen D, Wens I, Eijnde BO (2019) Exercise-induced (2014) Exercise training improves functional sympatholysis in
lactate responses in multiple sclerosis: a retrospective analysis. spontaneously hypertensive rats through a nitric oxide-dependent
NeuroRehabilitation 45(1):99–106. https://​d oi.​o rg/​1 0.​3 233/​ mechanism. Am J Physiol Heart Circ Physiol 307(2):H242-251.
NRE-​192740 https://​doi.​org/​10.​1152/​ajphe​art.​00103.​2014
Lee BS, Kim KA, Kim JK, Nho H (2020) Augmented hemodynamic Mizuno M, Iwamoto GA, Vongpatanasin W, Mitchell JH, Smith SA
responses in obese young men during dynamic exercise: role (2015) Dynamic exercise training prevents exercise pressor reflex
of the muscle metaboreflex. Int J Environ Res Public Health. overactivity in spontaneously hypertensive rats. Am J Physiol
https://​doi.​org/​10.​3390/​ijerp​h1719​7321 Heart Circ Physiol 309(5):H762-770. https://​doi.​org/​10.​1152/​
Magnani S, Olla S, Pau M, Palazzolo G, Tocco F, Doneddu A, Mar- ajphe​art.​00358.​2015
celli M, Loi A, Corona F, Corona F, Coghe G, Marrosu MG, Mostoufi-Moab S, Widmaier EJ, Cornett JA, Gray K, Sinoway LI
Concu A, Cocco E, Marongiu E, Crisafulli A (2016) Effects (1998) Forearm training reduces the exercise pressor reflex dur-
of six months training on physical capacity and metaboreflex ing ischemic rhythmic handgrip. J Appl Physiol 84(1):277–283.
activity in patients with multiple sclerosis. Front Physiol 7:531. https://​doi.​org/​10.​1152/​jappl.​1998.​84.1.​277
https://​doi.​org/​10.​3389/​fphys.​2016.​00531 Munch GW, Iepsen UW, Ryrso CK, Rosenmeier JB, Pedersen BK,
Magnani S, Roberto S, Sainas G, Milia R, Palazzolo G, Cugusi Mortensen SP (2018) Effect of 6 wk of high-intensity one-legged
L, Pinna V, Doneddu A, Kakhak SAH, Tocco F, Mercuro G, cycling on functional sympatholysis and ATP signaling in patients
Crisafulli A (2018) Metaboreflex-mediated hemodynamic with heart failure. Am J Physiol Heart Circ Physiol 314(3):H616–
abnormalities in individuals with coronary artery disease with- H626. https://​doi.​org/​10.​1152/​ajphe​art.​00379.​2017
out overt signs or symptoms of heart failure. Am J Physiol Heart Negrao CE, Rondon MU, Tinucci T, Alves MJ, Roveda F, Braga
Circ Physiol 314(3):H452–H463. https://​doi.​org/​10.​1152/​ajphe​ AM, Reis SF, Nastari L, Barretto AC, Krieger EM, Middlekauff
art.​00436.​2017 HR (2001a) Abnormal neurovascular control during exercise is
Mark AL, Victor RG, Nerhed C, Wallin BG (1985) Microneurographic linked to heart failure severity. Am J Physiol Heart Circ Physiol
studies of the mechanisms of sympathetic nerve responses to static 280(3):H1286-1292. https://d​ oi.o​ rg/1​ 0.1​ 152/a​ jphea​ rt.2​ 001.2​ 80.3.​
exercise in humans. Circ Res 57(3):461–469. https://​doi.​org/​10.​ H1286
1161/​01.​res.​57.3.​461 Negrao CE, Trombetta IC, Batalha LT, Ribeiro MM, Rondon MU,
Marongiu E, Olla S, Magnani S, Palazzolo G, Sanna I, Tocco F, Tinucci T, Forjaz CL, Barretto AC, Halpern A, Villares SM
Marcelli M, Loi A, Corona F, Mulliri G, Concu A, Crisafulli A (2001b) Muscle metaboreflex control is diminished in normoten-
(2015) Metaboreflex activity in multiple sclerosis patients. Eur sive obese women. Am J Physiol Heart Circ Physiol 281(2):H469-
J Appl Physiol 115(12):2481–2490. https://​doi.​org/​10.​1007/​ 475. https://​doi.​org/​10.​1152/​ajphe​art.​2001.​281.2.​H469
s00421-​015-​3271-0 Notarius CF, Atchison DJ, Floras JS (2001) Impact of heart failure and
McAllister RM, Kimani JK, Webster JL, Parker JL, Laughlin MH exercise capacity on sympathetic response to handgrip exercise.
(1996) Effects of exercise training on responses of peripheral and Am J Physiol Heart Circ Physiol 280(3):H969-976. https://​doi.​
visceral arteries in swine. J Appl Physiol 80(1):216–225. https://​ org/​10.​1152/​ajphe​art.​2001.​280.3.​H969
doi.​org/​10.​1152/​jappl.​1996.​80.1.​216 Notarius CF, Millar PJ, Keir DA, Murai H, Haruki N, O’Donnell E,
Michelini LC, O’Leary DS, Raven PB, Nobrega AC (2015) Neural Marzolini S, Oh P, Floras JS (2019) Training heart failure patients
control of circulation and exercise: a translational approach dis- with reduced ejection fraction attenuates muscle sympathetic
closing interactions between central command, arterial barore- nerve activation during mild dynamic exercise. Am J Physiol
flex, and muscle metaboreflex. Am J Physiol Heart Circ Physiol Regul Integr Comp Physiol 317(4):R503–R512. https://​doi.​org/​
309(3):H381-392. https://​doi.​org/​10.​1152/​ajphe​art.​00077.​2015 10.​1152/​ajpre​gu.​00104.​2019
Middlekauff HR, Sinoway LI (2007) Increased mechanoreceptor stim- Nystoriak MA, Bhatnagar A (2018) Cardiovascular effects and benefits
ulation explains the exaggerated exercise pressor reflex seen in of exercise. Front Cardiovasc Med 5:135. https://d​ oi.o​ rg/1​ 0.3​ 389/​
heart failure. J Appl Physiol 102(1):492–494. https://​doi.​org/​10.​ fcvm.​2018.​00135
1152/​jappl​physi​ol.​00994.​2006 O’Leary DS, Sala-Mercado JA, Augustyniak RA, Hammond RL, Rossi
Middlekauff HR, Nitzsche EU, Hoh CK, Hamilton MA, Fonarow GC, NF, Ansorge EJ (2004) Impaired muscle metaboreflex-induced
Hage A, Moriguchi JD (2000) Exaggerated renal vasoconstriction increases in ventricular function in heart failure. Am J Physiol
during exercise in heart failure patients. Circulation 101(7):784– Heart Circ Physiol 287(6):H2612-2618. https://​doi.​org/​10.​1152/​
789. https://​doi.​org/​10.​1161/​01.​cir.​101.7.​784 ajphe​art.​00604.​2004
Milia R, Roberto S, Marongiu E, Olla S, Sanna I, Angius L, Bassareo O’Leary DS, Senador D, Augustyniak RA (2019) Muscle metabore-
P, Pinna M, Tocco F, Concu A, Crisafulli A (2014) Improvement flex-induced central blood volume mobilization in heart failure.
in hemodynamic responses to metaboreflex activation after one Am J Physiol Heart Circ Physiol 316(5):H1047–H1052. https://​
year of training in spinal cord injured humans. Biomed Res Int doi.​org/​10.​1152/​ajphe​art.​00805.​2018
2014:893468. https://​doi.​org/​10.​1155/​2014/​893468 Piepoli M, Clark AL, Volterrani M, Adamopoulos S, Sleight P, Coats
Milia R, Roberto S, Mulliri G, Loi A, Marcelli M, Sainas G, Milia N, AJ (1996) Contribution of muscle afferents to the hemodynamic,
Marongiu E, Crisafulli A (2015) Effect of aging on hemodynamic autonomic, and ventilatory responses to exercise in patients with

13
European Journal of Applied Physiology

chronic heart failure: effects of physical training. Circulation ischemia. Am J Physiol Regul Integr Comp Physiol 304(8):R657-
93(5):940–952. https://​doi.​org/​10.​1161/​01.​cir.​93.5.​940 663. https://​doi.​org/​10.​1152/​ajpre​gu.​00601.​2012
Powers SK, Radak Z, Ji LL (2016) Exercise-induced oxidative stress: Sterns DA, Ettinger SM, Gray KS, Whisler SK, Mosher TJ, Smith
past, present and future. J Physiol 594(18):5081–5092. https://d​ oi.​ MB, Sinoway LI (1991) Skeletal muscle metaboreceptor exercise
org/​10.​1113/​JP270​646 responses are attenuated in heart failure. Circulation 84(5):2034–
Prodel E, Fisher JP, Barbosa TC, Fernandes IA, Nobrega AC, Vianna 2039. https://​doi.​org/​10.​1161/​01.​cir.​84.5.​2034
LC (2016) Relationship between aortic augmentation index and Sundblad P, Kolegard R, Rullman E, Gustafsson T (2018) Effects
blood pressure during metaboreflex activation in healthy young of training with flow restriction on the exercise pressor reflex.
men. Blood Press Monit 21(5):288–294. https://​doi.​org/​10.​1097/​ Eur J Appl Physiol 118(9):1903–1909. https://​doi.​org/​10.​1007/​
MBP.​00000​00000​000202 s00421-​018-​3911-2
Ray CA, Carrasco DI (2000) Isometric handgrip training reduces arte- Teixeira AL, Fernandes IA, Vianna LC (2020) Cardiovascular control
rial pressure at rest without changes in sympathetic nerve activity. during exercise: the connectivity of skeletal muscle afferents to
Am J Physiol Heart Circ Physiol 279(1):H245-249. https://​doi.​ the brain. Exerc Sport Sci Rev 48(2):83–91. https://​doi.​org/​10.​
org/​10.​1152/​ajphe​art.​2000.​279.1.​H245 1249/​JES.​00000​00000​000218
Roberto S, Marongiu E, Pinna M, Angius L, Olla S, Bassareo P, Tocco Thomas GD (2015) Functional sympatholysis in hypertension. Auton
F, Concu A, Milia R, Crisafulli A (2012) Altered hemodynamics Neurosci: Basic Clin 188:64–68. https://d​ oi.o​ rg/1​ 0.1​ 016/j.a​ utneu.​
during muscle metaboreflex in young type 1 diabetes patients. 2014.​10.​019
J Appl Physiol 113(8):1323–1331. https://​doi.​org/​10.​1152/​jappl​ Trombetta IC, Batalha LT, Rondon MU, Laterza MC, Kuniyoshi FH,
physi​ol.​00280.​2012 Gowdak MM, Barretto AC, Halpern A, Villares SM, Negrao
Saito M, Iwase S, Hachiya T (2009) Resistance exercise training CE (2003) Weight loss improves neurovascular and muscle
enhances sympathetic nerve activity during fatigue-inducing metaboreflex control in obesity. Am J Physiol Heart Circ Physiol
isometric handgrip trials. Eur J Appl Physiol 105(2):225–234. 285(3):H974-982. https://​doi.​org/​10.​1152/​ajphe​art.​01090.​2002
https://​doi.​org/​10.​1007/​s00421-​008-​0893-5 Vianna LC, Fernandes IA, Barbosa TC, Teixeira AL, Nobrega ACL
Saltin B, Mortensen SP (2012) Inefficient functional sympatholysis (2018) Capsaicin-based analgesic balm attenuates the skel-
is an overlooked cause of malperfusion in contracting skeletal etal muscle metaboreflex in healthy humans. J Appl Physiol
muscle. J Physiol 590(24):6269–6275. https://​doi.​org/​10.​1113/​ 125(2):362–368. https://d​ oi.o​ rg/1​ 0.1​ 152/j​ applp​ hysio​ l.0​ 0038.2​ 018
jphys​iol.​2012.​241026 Victor RG, Seals DR (1989) Reflex stimulation of sympathetic out-
Sidhu SK, Weavil JC, Rossman MJ, Jessop JE, Bledsoe AD, Buys flow during rhythmic exercise in humans. Am J Physiol 257(6
MJ, Supiano MS, Richardson RS, Amann M (2019) Exercise Pt 2):H2017-2024. https://​doi.​org/​10.​1152/​ajphe​art.​1989.​257.6.​
pressor reflex contributes to the cardiovascular abnormalities H2017
characterizing: hypertensive humans during exercise. Hyperten- Victor RG, Seals DR, Mark AL (1987) Differential control of heart rate
sion 74(6):1468–1475. https://​doi.​org/​10.​1161/​HYPER​TENSI​ and sympathetic nerve activity during dynamic exercise. Insight
ONAHA.​119.​13366 from intraneural recordings in humans. J Clin Invest 79(2):508–
Smith SA, Mitchell JH, Naseem RH, Garry MG (2005a) Mechanoreflex 516. https://​doi.​org/​10.​1172/​JCI11​2841
mediates the exaggerated exercise pressor reflex in heart failure. Wang HJ, Li YL, Gao L, Zucker IH, Wang W (2010a) Alteration
Circulation 112(15):2293–2300. https://​doi.​org/​10.​1161/​CIRCU​ in skeletal muscle afferents in rats with chronic heart failure. J
LATIO​NAHA.​105.​566745 Physiol 588(Pt 24):5033–5047. https://​doi.​org/​10.​1113/​jphys​iol.​
Smith SA, Williams MA, Mitchell JH, Mammen PP, Garry MG 2010.​199562
(2005b) The capsaicin-sensitive afferent neuron in skeletal mus- Wang HJ, Pan YX, Wang WZ, Gao L, Zimmerman MC, Zucker IH,
cle is abnormal in heart failure. Circulation 111(16):2056–2065. Wang W (2010b) Exercise training prevents the exaggerated
https://​doi.​org/​10.​1161/​01.​CIR.​00001​62473.​10951.​0A exercise pressor reflex in rats with chronic heart failure. J Appl
Smith JR, Hart CR, Ramos PA, Akinsanya JG, Lanza IR, Joyner Physiol 108(5):1365–1375. https://​doi.​org/​10.​1152/​jappl​physi​ol.​
MJ, Curry TB, Olson TP (2020) Metabo- and mechanoreceptor 01273.​2009
expression in human heart failure: relationships with the locomo- Wang HJ, Li YL, Zucker IH, Wang W (2012) Exercise training prevents
tor muscle afferent influence on exercise responses. Exp Physiol skeletal muscle afferent sensitization in rats with chronic heart
105(5):809–818. https://​doi.​org/​10.​1113/​EP088​353 failure. Am J Physiol Regul Integr Comp Physiol 302(11):R1260-
Somers VK, Leo KC, Shields R, Clary M, Mark AL (1992) Forearm 1270. https://​doi.​org/​10.​1152/​ajpre​gu.​00054.​2012
endurance training attenuates sympathetic nerve response to iso-
metric handgrip in normal humans. J Appl Physiol 72(3):1039– Publisher’s Note Springer Nature remains neutral with regard to
1043. https://​doi.​org/​10.​1152/​jappl.​1992.​72.3.​1039 jurisdictional claims in published maps and institutional affiliations.
Spranger MD, Sala-Mercado JA, Coutsos M, Kaur J, Stayer D,
Augustyniak RA, O’Leary DS (2013) Role of cardiac output ver-
sus peripheral vasoconstriction in mediating muscle metaboreflex
pressor responses: dynamic exercise versus postexercise muscle

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