Exercise training is a well-established intervention to improve physical capacity in many types of diseases. Beneficial effects have been reported in heart failure, chronic ischemic heart disease, hypertension, diabetes, and other metabolic conditions. For example, training has been found capable to improve physical capacity and quality of life in heart failure, to reduce blood pressure, to increase survival after infarction, and to increase insulin sensitivity (Pedersen and Saltin, 2015). Recently, improvements in symptoms and quality of life have also been demonstrated in neurological pathologies. Among others, Multiple Sclerosis (MS) has been found to be positively affected by physical exercise, as peak oxygen uptake and oxygen pulse were found improved after periods of training, thereby suggesting an increase exercise tolerance in these patients. Moreover, training may induce a positive effect on MS fatigue (Rampello et al., 2007; Dalgas et al., 2008; Andreasen et al., 2011; Pedersen and Saltin, 2015). However, data on the effect of supervised physical training on hemodynamic regulation during exercise in MS patients are scarce.

One of the key symptoms in MS is exertion fatigue, which is reported by 50–60% of these patients as their most disturbing problem (Tartaglia et al., 2005; Mollaouğlu and Űstűn, 2009; Andreasen et al., 2011). Several reasons might be responsible for this phenomenon. Of these, cardiovascular dysregulation during exercise has been observed in some investigations dealing with MS (Ng et al., 2000; Sanya et al., 2005). Some individuals with MS may have impairment of the autonomically-mediated blood pressure response during isometric exercise, and this phenomenon has been suggested to be related to symptomatic fatigue (Ng et al., 2000).

In healthy subjects, hemodynamic regulation during exercise is achieved by the integration of signals arising from mechano- and metabo-receptors within the working muscle and central command activation, which together concur in increasing sympathetic activity (O'Leary et al., 2004; Amann et al., 2011; Nobrega et al., 2014). The increased sympathetic activity is modulated in turn by the baroreflex activation, which dampens any excessive increment in sympathetic tone (Crisafulli et al., 2015). Several clues suggest that MS can influence these cardiovascular reflexes, thereby impairing the hemodynamic response during exertion (Ng et al., 2000; Flackenecher et al., 2001; Sanya et al., 2005; Marongiu et al., 2013). For instance, it was found impaired baroreflex control of the HR rate in MS patients, as well as impairment of the sympathetic-mediated baroreflex control of blood vessels, which together can explain the high incidence of orthostatic dizziness in these patients (Sanya et al., 2005). Moreover, our group has recently demonstrated that MS patients had an altered hemodynamic response to metaboreflex activation (Marongiu et al., 2015). This response resembled that showed by patients with cardiovascular and metabolic disease, where the target blood pressure is reached mainly by means of vasoconstriction (Piepoli et al., 2008; Delaney et al., 2010; Dipla et al., 2010; Choi et al., 2013; Crisafulli et al., 2013; Milia et al., 2015b). In healthy subjects, during the metaboreflex, a cardiac output-mediated mechanism is primarily responsible for the normal increase in mean blood pressure (MBP; Crisafulli et al., 2003, 2008; Delaney et al., 2010; Roberto et al., 2012; Spranger et al., 2013). In the investigation by Marongiu et al. (2015), it was hypothesized that physical deconditioning was responsible for the exaggerated vasoconstriction and the increase in SVR found in MS during the metaboreflex. This hypothesis is supported by previous findings suggesting that deconditioning may play a key role in the impaired exercise tolerance of people with MS (Rampello et al., 2007). Moreover, others have reported a shift in fiber type composition from type I fibers to a greater proportion of type II fibers in MS patients as a consequence of deconditioning (Dalgas et al., 2008). This occurrence may potentially have an impact on the metaboreflex activation as metabolites production is related to fiber type, with type II producing higher amounts of end-products than type I. It is then reasonable to assume that a shift from type I to type II in the muscle fiber composition would result in a more robust metaboreflex activity.

Therefore, we wondered whether a physical training program, along with its effects on physical capacity, could also counteract the reported cardiovascular dysregulation to the metaboreflex in these patients. To address this question, two groups of patients with MS were studied: one underwent a program of adapted physical activity (APA) and the other did not. The cardiovascular response to the muscle metaboreflex was then assessed at baseline, at three, at 6 months from the beginning of the study. To detect whether or not improvements in the capacity to exercise were paralleled by improvements in the hemodynamic response to the metaboreflex activation, indices of physical capacity were also evaluated.

Four of the 25 patients (two from the MSIT and two from the MSCTL group, one male and one female for each group) abandoned the study. In detail, three of them had a clinical deterioration which caused a substantial increment in the EDSS scale, while one had a car accident which caused immobilization for 3 months. Thus, data shown are from 11 MSIT patients and 10 MSCTL patients. Their physical characteristics, respectively, for MSIT and MSCTL were: age 47.8 ± 10.8 and 40.7 ± 14 years (p = 0.20), body mass 68.5 ± 17.6 kg and 64.5 ± 10.1 kg (p = 0.50), height 168.4 ± 8 cm and 166 ± 9.2 cm (p = 0.53). There was no difference in any parameters between groups. Table 1 shows data from the CPT-test collected at T0. Data of VO₂ are expressed indexed by body weight. No statistical differences were observed between groups. Table 2 reports mean values of hemodynamic parameters recorded during rest periods preceding the PEMI and the CER tests at T0, T3, and T6, respectively. Statistics did not evidence any difference due to group or condition. Table 3 shows hemodynamic data collected at the third minute of recovery of the PEMI and the (CER) tests. Responses in parameters are also shown.

Figure 1 depicts the variation with respect to T0 in CPT parameters collected at T3 and T6. All variables were significantly affected by group assignment, as in the MSIT group all variables gathered at anaerobic threshold and at maximum workload showed a significant main effect due to group.

Figures 2–4 report hemodynamic responses obtained during the periods of metaboreflex activation, i.e., the difference between the variable's levels at the third minute of recovery from the PEMI test minus the level at the third minute of recovery from the CER test. None of the parameters were affected by group or time at T0, T3, and T6. Notably, the SVR response was always positive (i.e., vascular resistance increased during the PEMI in comparison to the CER test) with the exception of the MSIT group at T6, when SVR actually decreased. However, statistical significance was not reached.

This investigation aimed to ascertain whether the hemodynamic response to metaboreflex activation was positively changed by a period of adapted physical activity. Our reasoning was that physical deconditioning, along with its effect on physical capacity, could counteract the vasoconstriction, and the increase in SVR response shown by MS patients during the metaboreflex. In a recent investigation conducted in our laboratory to discover whether MS patients had a normal hemodynamic response to the metaboreflex, it was found that these patients exaggeratedly increased SVR. It was speculated that this phenomenon was the consequence of the inactive lifestyle of these patients because of their disease (Marongiu et al., 2015). Thus, an intervention able to increase physical capacity may hypothetically counteract this tendency to excessively vasoconstrict the arteriolar bed.

However, results of the present investigation contradict this hypothesis. Indeed, notwithstanding MSIT group patients successfully increased their parameters related to physical capacity as compared to the MSCTL group, this phenomenon was not paralleled by any variation in the hemodynamic response to the metaboreflex. Actually, SVR was unaffected by the training program and no significant variations were detected in neither SV nor CO response in both groups in study.

Our data are in accordance with the concept that a physical intervention is able to improve exercise capacity in MS patients (Ponichtera-Mulcare, 1993; Petajan and White, 1999; Rampello et al., 2007; Dalgas et al., 2008; Andreasen et al., 2011). In reality, the MSIT group substantially increased all CPT parameters related to physical capacity after the period of training in comparison with the MSCTL group, as testified by HR, W, VO₂, and VE gathered at both AT and maximum workload.

No significant variation in the Expanded Disability Status scale score, neither in the MSCTL nor in the MSIT group was observed. Therefore, the significant improvement in exercise capacity found in the present study was very likely the result of the physical intervention and the reduced sedentary lifestyle. This occurrence confirms the hypothesis that an active lifestyle is a useful behavior to counteract the negative consequences of MS in terms of physical capacity, fatigue perception and physical fitness (Dalgas et al., 2008; Andreasen et al., 2011). Moreover, this finding supports the concept that a sedentary lifestyle is harmful in MS and that sedentary habits worsen the outcome in terms of physical capacity and of the possibility to perform daily-life activities.

Despite the fact that the physical intervention positively affected the physical capacity of patients of the MSIT group, it was unable to significantly change their hemodynamic response during the metaboreflex in comparison with the MSCTL group. Actually, the hemodynamic adjustment during the metaboreflex remained similar between the two groups in study and no significant difference was detected between them, although it should be pointed out that there was a wide inter-subject variability, as testified by the large parameters SD. A study with a larger sample size would be useful to ascertain whether reducing variability would result in a different outcome. Furthermore, the physical intervention could not reverse the tendency to increase SVR to reach the target blood pressure during the metaboreflex, with the exception of the MSIT at T6, when the response in this parameter was on average negative. The SVR response found in the present investigation was very similar to that reported in a recent study conducted in our Laboratory in 43 patients with MS (Marongiu et al., 2015). In detail, it was reported that patients with MS on average increased SVR by 137.6 ± 300.5 dyne·s^−1·cm⁻⁵ whereas the mean response of healthy controls was −14.3 ± 240.6 dyne·s^−1·cm⁻⁵, thereby indicating the absence of vasoconstriction in healthiness. It should however be noticed that, notwithstanding the study by Marongiu et al. (2015) was conducted in a numerous sample (43 patients), a large SD was detected, which suggests that there is a wide inter-subject variability in the SVR response in MS patients.

The fact that the cardiovascular response during the metaboreflex activation was not improved notwithstanding the enhanced exercise capacity suggests that the hemodynamics during the metaboreflex was not related to exertional fatigue in MS patients. It has been hypothesized that the discharges of afferent group III and IV nerve endings in the muscle, which are responsible for the metaboreflex eliciting, are at least in part also responsible for the sensation of fatigue. Feedback from these nervous afferents potentially inhibits central motor drive and facilitates central fatigue, thereby limiting exercise performance (Amann et al., 2008; Mulliri et al., 2016). Thus, fatigue may be hypothetically related to the level of metaboreflex activation. Since in the present investigation we did not find any different hemodynamics before and after the period of training, it is conceivable that the level of metaboreflex activity was similar in these two conditions. However, exercise capacity was higher after training, thereby indicating that probably deconditioning is more important than cardiovascular dys-regulation in the genesis of fatigue in MS patients.

The hemodynamic scenario depicted in the present study resembled the typical response observed in several diseases such as heart failure, obesity, metabolic syndrome, and hypertension, where an excessive sympathetic tone has often been reported (Crisafulli et al., 2007; Delaney et al., 2010; Milia et al., 2015b), whereas in normal subjects vasoconstriction is limited and the target blood pressure is reached mainly by a cardiac output-mediated mechanism (Crisafulli et al., 2003).

It was hypothesized that alterations in skeletal muscle morphology, metabolism, blood flow, and function due to physical deconditioning are important determinants in the altered hemodynamic response to exercise and metaboreflex activation in patients with heart failure. This is known as “the muscle hypothesis” of heart failure (Piepoli and Crisafulli, 2014). Of note, in these patients it appears that physical training can partially reverse this condition (Piepoli et al., 2006), since improving exercise capacity is accompanied by a gradual reduction in metaboreflex-induced vasoconstriction (Piepoli and Crisafulli, 2014). One possible mechanism is that exercise can improve muscle aerobic metabolism, thereby reducing anaerobic end-products accumulation, which are responsible for metaboreflex activation. Moreover, training can counteract the effect of sedentary lifestyle, which induces a shift from type I to type II in muscle fibers composition. It is well known that type II fibers produce a larger amount of metabolic by-products than type I, and in turn this fact can cause an increase in metaboreflex activity with altered hemodynamic response (Piepoli et al., 2008). It is then conceivable that our cohorts of MS patients showed an altered hemodynamic response to the metaboreflex because of a chronic muscle disuse. Actually, it has been reported a shift in fiber type composition from type I fibers to a greater proportion of type II fibers in MS patients as a consequence of deconditioning (Dalgas et al., 2008).

It is however a matter of fact that in the present study there was the lack of any significant improvement in the hemodynamic response to the metaboreflex, although future research with more patients is warranted. It should be kept in mind that MS is a demyelinating disease, where the progression of nervous fibers degeneration is unpredictable and does not depend on patients' physical capacity. Hence, it is possible that the lack of improvement in the hemodynamic response during the metaboreflex could simply depend on irreversible damages at the level of central nervous system. For instance, lesions at the level of the spinal cord, especially at the dorsal horn, where there are important sensory inputs for the metaboreflex, could account for the altered hemodynamics that these patients showed after the period of training.

SM, SO, EC, EM, AC conceived the study, conducted experiments, designed and wrote the paper. MP, GP, FT, MGM, and AC conceived the study, designed and wrote the paper. AD, MM, AL, FeC, FrC, and GC conducted experiments, designed and wrote the paper. All authors read and approved the final version of the manuscript.

This study was supported by the University of Cagliari, the Regione Sardegna (legge regionale n°7 Agosto 2007, annualità 2011), and the Italian Ministry of Scientific Research.