Omid Razi

Bakhtyar Tartibian

Ana Maria Teixeira

Nastaran Zamani

Karuppasamy Govindasamy

Katsuhiko Suzuki

Ismail Laher

Hassane Zouhal
email: hassane.zouhal@univ-rennes2.fr

Prof. Katsuhiko Suzuki

Thermal dysregulation in patients with multiple sclerosis during SARS-CoV-2 infection. The potential therapeutic role of exercise

Keywords: Multiple sclerosis, exercise, thermoregulation, sweat gland, SARS-CoV-2, ANS, Autonomic nervous system, APN, Adiponectin, CNS, Central nervous system, COVID-19, Coronavirus disease-2019, EDHF, Endothelial-derived hyperpolarizing factor, eNOS, Endothelial nitric oxide synthase, MS, Multiple sclerosis, NLRP3, NLR family pyrin domain containing 3, NO, Nitric oxide, PACAP, Pituitary adenylate cyclase-activating polypeptide, PAMPs, Pathogen-associated molecular patterns, PGs, Prostaglandins, PGE 2 , Prostaglandin E 2, ROS, Reactive oxygen species, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, SNS, Sympathetic nervous system, TRPV-1, Transient receptor potential vanilloid type 1, VDP, Vascular-dilating prostanoids, VEGF, Vascular endothelial growth factor, VIP, Vasoactive intestinal peptide

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Multiple sclerosis (MS) is a neurodegenerative disease characterized by lesions of the central nervous system (CNS). A unique feature of this autoimmune disease is the high prevalence (60-80%) of temperature sensitivity, where neurological signs are exacerbated by increases in environmental or internal body temperatures. The regulation of a near constant body temperature within a physiological range is required for survival and daily function [START_REF] Corbett | Adaptation to heat and exercise performance under cooler conditions: a new hot topic[END_REF].

Body temperature is composed of central and skin temperature [START_REF] Gisolfi | The hot brain: survival, temperature, and the human body[END_REF][START_REF] Lim | Human thermoregulation and measurement of body temperature in exercise and clinical settings[END_REF][START_REF] Lim | Systemic inflammation mediates the effects of endotoxemia in the mechanisms of heat stroke[END_REF]. Core temperature is centrally regulated by the brain in response to changes in thermal balance [START_REF] Gisolfi | The hot brain: survival, temperature, and the human body[END_REF][START_REF] Lim | Fundamental Concepts of Human Thermoregulation and Adaptation to Heat: A Review in the Context of Global Warming[END_REF]. Venous blood temperature and afferent signals from thermo-sensitive nerves on the body surface act to regulate autonomic nervous and behavioral responses to regulate body temperature [START_REF] Lim | Human thermoregulation and measurement of body temperature in exercise and clinical settings[END_REF]. The control of temperature in the body results from a balance between heat gain and its dissipation [START_REF] Lim | Fundamental Concepts of Human Thermoregulation and Adaptation to Heat: A Review in the Context of Global Warming[END_REF].

Thermoregulation in humans is accomplished by several independent loops of the thermoregulatory reflex. Peripheral receptors are activated by increases in skin and core temperatures, and activate afferent nerves to signal the preoptic anterior hypothalamus as the integrating center. After integrating the thermal-afferent information, increased efferent nerve outflows lead to activating the thermal-effector responses that result in sweating and cutaneous vasodilation consequent to releasing of acetylcholine and other co-transmitters such as vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), vascular-dilating prostanoids (VDP), substance P (SP), and channels of transient receptor potential vanilloid type 1 (TRPV-1) [START_REF] Francisco | Cutaneous active vasodilation as a heat loss thermoeffector[END_REF][START_REF] Gagnon | Plasma hyperosmolality attenuates skin sympathetic nerve activity during passive heat stress in humans[END_REF][START_REF] Taylor | Human heat adaptation[END_REF][START_REF] White | Hypothermia in multiple sclerosis[END_REF]. Disturbances of this thermoregulatory reflex occurs in some diseases such as MS, a disease of demyelination, which affects neural conduction.

Thermal fluctuations impact neural conduction [START_REF] Morrison | Central nervous system regulation of body temperature[END_REF]. Inactivity reduces the reactivity of cutaneous small-vessels, and increases core temperature [START_REF] Wang | Effects of exercise training and detraining on cutaneous microvascular function in man: the regulatory role of endothelium-dependent dilation in skin vasculature[END_REF]. This could underlie the high sensitivity of patients with MS to increases in core body temperature induced by exogenous agents such as viral infections. Individuals infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) also experience increased core body temperatures, which can exacerbate temperature dysregulation in patients with preexisting dysregulation of body temperature. We review temperature dysregulation in patients with MS and the added burden of the coronavirus disease-19 (COVID-19) pandemic. In addition, we also discuss the adaptions produced by regular physical exercise as an adjunct procedure to mitigate the effects of heat in patients with MS infected the SARS-CoV-2.

Thermal dysregulation in MS patients as a challenge during SARS-CoV-2 infection

MS is the primary cause of neuronal dysfunction in juveniles [START_REF] Edmonds | Palliative care for people severely affected by multiple sclerosis: evaluation of a novel palliative care service[END_REF]. The autonomic nervous system (ANS) is severely impacted in individuals with MS [START_REF] Gunal | Autonomic dysfunction in multiple sclerosis: correlation with disease-related parameters[END_REF], where dysfunction of sympathetic and parasympathetic nerves is associated with a range of diverse clinical disabilities [START_REF] Flachenecker | Autonomic dysfunction in multiple sclerosis is related to disease activity and progression of disability[END_REF][START_REF] Habek | Immune and autonomic nervous system interactions in multiple sclerosis: clinical implications[END_REF]. Autonomic dysfunction in MS is related to lesions in the periventricular region of the fourth ventricle of the brainstem and medulla [START_REF] Adamec | Autonomic dysfunction in multiple sclerosis[END_REF]. Autonomic dysfunction results from both demyelination and also axonal loss [START_REF] De Seze | Autonomic dysfunction in multiple sclerosis: cervical spinal cord atrophy correlates[END_REF], affecting cardiovascular (66% of patients) [START_REF] Acevedo | Cardiovascular dysfunction inmultiple sclerosis[END_REF][START_REF] Mincu | Cardiovascular dysfunction in multiple sclerosis[END_REF], bladder (97% of patients) [START_REF] Haensch | Autonomic dysfunction in multiple sclerosis[END_REF], sexual function (80% of patients) [START_REF] Tepavcevic | The impact of sexual dysfunction on the quality of life measured by MSQoL-54 in patients with multiple sclerosis[END_REF], bowel (43% of patients) [START_REF] Hinds | Prevalence of bowel dysfunction in multiple sclerosis: a population survey[END_REF], sleep (50% of patients) [START_REF] Bamer | Prevalence of sleep problems in individuals with multiple sclerosis[END_REF], heat sensitivity (60-90% of patients) [START_REF] Gallup | Yawning, sleep, and symptom relief in patients with multiple sclerosis[END_REF] and also altered motor symptoms (e.g., fatigue) (thermoregulation).

Hypothalamic lesions can result in both hyperthermia and hypothermia [START_REF] Linker | Core hypothermia in multiple sclerosis: case report with magnetic resonance imaging localization of a thalamic lesion[END_REF][START_REF] White | Hypothermia in multiple sclerosis[END_REF]. Increasing core body temperature occurs commonly in patients with MS and can be due to interruptions in central sudomotor pathways which originate from the preoptic hypothalamic area and descend to the intermediolateral of the spinal cord to exit from the central nervous system (CNS) to innervate sweat glands that can lower core temperature [START_REF] Adamec | Autonomic dysfunction in multiple sclerosis[END_REF][START_REF] Saari | Sweating impairment in patients with multiple sclerosis[END_REF]. Impairment of this pathway worsens neurological signs and symptoms and in severe cases can increase heat sensitivity or Uhthoff phenomenon/syndrome, which describes a transient worsening of neurological symptoms (caused by hot weather, exercise, fever, being in a heated environment etc.) due to demyelination in MS [START_REF] Jain | Wilhelm Uhthoff and Uhthoff's phenomenon[END_REF]. Up to 60 to 80% of MS patients experience this phenomenon that can be triggered by increases in core temperature by as little as 0.5˚C, resulting in transient symptoms such as visual blurring [START_REF] Cianfrone | Temperature-Dependent Auditory Neuropathy: Is it an Acoustic Uhthoff-like Phenomenon?; A Case Report[END_REF][START_REF] Filingeri | Afferent thermosensory function in relapsing-remitting multiple sclerosis following exercise-induced increases in body temperature[END_REF][START_REF] Jain | Wilhelm Uhthoff and Uhthoff's phenomenon[END_REF][START_REF] Syndulko | Effects of temperature in multiple sclerosis: a review of the literature[END_REF][START_REF] Wilson | Aerobic training improves in vivo cholinergic responsiveness but not sensitivity of eccrine sweat glands[END_REF]. The first report on visual blurring with exercise as a heat stressor was described in 1890 by Uhthoff, who attributed it to increases in core body temperature, leading to the avoidance of exercise by patients with MS [START_REF] Baker | Multiple sclerosis and thermoregulatory dysfunction[END_REF][START_REF] Frohman | Uhthoff's phenomena in MS-clinical features and pathophysiology[END_REF].

Thermal sensitivity is usually measured in patients with MS by responses to heat (e.g., using hot water immersion, heat lamp, and heat cabinet) and evaluating emerging or worsening neurological signs [START_REF] Leavitt | Warmer outdoor temperature is associated with task-related increased BOLD activation in patients with multiple sclerosis[END_REF][START_REF] Nelson | Effects of induced hyperthermia on some neurological diseases[END_REF][START_REF] Nelson | The effects of induced hyperthermia on patients with multiple sclerosis[END_REF]. Initial studies on healthy individuals, people with neurological disorders and patients with MS reported that two patients with MS died after exposure to increased body temperatures of up to 40 ˚C for 8-10 hours; patients with MS experienced motor weakness, amblyopia, and visual deficits following a heat stress. Such sensitivity in patients with MS even occurred after exposure one limb to temperature increase of up to ~ 0.5 ̊ C [START_REF] Guthrie | Visual and motor changes in multiple sclerosis as a result of induced temperature changes[END_REF][START_REF] Guthrie | Visual and motor changes in patients with multiple sclerosis: a result of induced changes in environmental temperature[END_REF]. A later study of responses to a heat stress (55-60 ̊ C) in patients with MS reported worsening of signs in 75% patients within 10-15 min [START_REF] Edmund | Visual and motor instability in multiple sclerosis[END_REF]. Another study indicated that clinical signs appeared in patients with MS after 8 min when body temperatures were increased by 0.8 ̊ C; clinical signs peaked when body temperature was increased by 1.7 ̊ C for 28 min [START_REF] Nelson | Effects of induced hyperthermia on some neurological diseases[END_REF]. Some studies also suggest that increased core body temperature in patients with MS could result from lowered sweating rates as well as delayed sweat initiation [START_REF] Krupp | Fatigue in multiple sclerosis, Multiple Sclerosis Therapeutics[END_REF][START_REF] Petajan | Recommendations for physical activity in patients with multiple sclerosis[END_REF], or having a higher sweat threshold [START_REF] Baker | Multiple sclerosis and thermoregulatory dysfunction[END_REF][START_REF] Huang | Autonomic dysfunction in multiple sclerosis: implications for exercise[END_REF][START_REF] Racosta | Autonomic dysfunction in multiple sclerosis[END_REF]. In addition, the reduction in sweating function in MS patients is largely due to decreased sweat output in individual sweat glands rather than to reduced gland recruitment (Davis et al., 2010a), and that 15 weeks of aerobic endurance was unable to improve sweat function in patients with MS. Thus, heat sensitivity is a characteristic feature of MS [START_REF] Davis | Pilocarpineinduced sweat gland function in individuals with multiple sclerosis[END_REF].

Regardless of being a frequent complaint in patients with MS, our understanding of how increases or decreases in body temperature contribute to worsening of MS symptoms is incomplete. However, as depicted in Figure 1, the most likely mechanisms underlying heat sensitivity and the exacerbation of the symptoms of MS can be summarized as follow: A) Demyelinated axons in brain lesions and peripheral neurons overexpress voltage-gated Na + (Na v ) channels, particularly α-subunits, throughout their length [START_REF] Smith | Sodium channels and multiple sclerosis: roles in symptom production, damage and therapy[END_REF][START_REF] Tartas | Anodal current intensities above 40 μA interfere with current-induced axon-reflex vasodilatation in human skin[END_REF]. There have been generally revealed 9 isoforms of this type of Na v channels (Na v 1.1 to 1.9). The isoforms of Na v 1.1, Na v 1.2, Na v 1.3, and Na v 1.6 extremely expressed in CNS [START_REF] Egri | A hot topic: temperature sensitive sodium channelopathies[END_REF]. These channels influence enormous characteristics of neurons including refractory phase and excitability of neurons. The contribution of these channels in neuronal electrogenesis is formed based on their different spatial distribution within the axon membrane, with high density in the axon membrane at the node of Ranvier and much lower density in other areas beneath myelin including paranodal and intermodal axon membrane [START_REF] Peles | Molecular domains of myelinated axons[END_REF][START_REF] Waxman | Demyelinating diseases-new pathological insights, new therapeutic targets[END_REF]. Sodium channels illustrate a dynamic changes either in normal CNS (during development) or in pathological CNS. It has been reported that MS patients and its animal model, experimental autoimmune encephalomyelitis (EAE), experience a plasticity in Na v channels in both expression and distribution levels. Notably, Na v 1.2 and 1.6 are the most isoforms undergoing increased expression and also they extended to the paranodal and juxtaparanodal areas [START_REF] Craner | Abnormal sodium channel distribution in optic nerve axons in a model of inflammatory demyelination[END_REF]Craner et al., 2004b). Increased Na v channels is associated with some changes in impulse conductance and hyperexcitibility and exacerbating the clinical signs of these patients is partly due to a persistent sodium current which may accompany neural damage and loss of axons that transfer information on central temperature to hypothalamus. Increased intracellular Na + will cause Ca 2+ dysregulation, including by acting on Na + /Ca 2+ exchange. Intracellular accrual of Ca 2+ initiates neural and axon damages through activating some catabolic enzymes, including proteases and calpains [START_REF] Agrawal | Mechanisms of secondary injury to spinal cord axons in vitro: role of Na+, Na (+)-K (+)-ATPase, the Na (+)-H+ exchanger, and the Na (+)-Ca2+ exchanger[END_REF][START_REF] Correale | Mechanisms of neurodegeneration and axonal dysfunction in progressive multiple sclerosis[END_REF]Craner et al., 2004a;Craner et al., 2004b;[START_REF] Stys | Noninactivating, tetrodotoxin-sensitive Na+ conductance in rat optic nerve axons[END_REF][START_REF] Stys | Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+ channels and Na (+)-Ca2+ exchanger[END_REF]. Upon losing the central and peripheral neurons, thus, MS patients in progressive phase of disease do not have an accurate perception of how extent their central body temperature has been increased. B) Roughly 20% of hypothalamic neurons are stratified as a thermal-sensitive neurons with high rates of action potential in proportional with other thermal-nonsensetive ones [START_REF] Wechselberger | Ionic channels and conductancebased models for hypothalamic neuronal thermosensitivity[END_REF]. These neurons not only respond to the temperature of hypothalamus but receive afferent synaptic inputs from skin and spinal thermorecptors; hence, they integrate the central and peripheral temperatures. Thermal sensitivity of these hypothalamic neurons partly results from some selective ionic channels [START_REF] Boulant | The effect of spinal and skin temperatures on the firing rate and thermosensitivity of preoptic neurones[END_REF][START_REF] Wechselberger | Ionic channels and conductancebased models for hypothalamic neuronal thermosensitivity[END_REF]. Normal function of neurons depends on regularly fire action potentials and maintenance resting membrane potentials. In this regard, potassium channels including two-pore domain K + (K2P) channels contribute to the steady outward leak of K + ions and consequent restoring of the rate of action potential [START_REF] Braun | Two-pore domain potassium channels: variation on a structural theme[END_REF]. Humans express 14 K2P channels which have been categorized into 5 subgroups [START_REF] Patel | Properties and modulation of mammalian 2P domain K+ channels[END_REF]. These channels play a leading role in establishing resting membrane potential, regulating potential duration and modulating the response to synaptic inputs [START_REF] Griffin | Cellular mechanisms for neuronal thermosensitivity in the rat hypothalamus[END_REF][START_REF] Patel | Properties and modulation of mammalian 2P domain K+ channels[END_REF][START_REF] Rush | The potassium A-current, low firing rates and rebound excitation in Hodgkin-Huxley models[END_REF].

Besides, the most majority of potassium channels extensively express in human brain [START_REF] Maingret | TREK-1 is a heat-activated background K+ channel[END_REF][START_REF] Patel | Properties and modulation of mammalian 2P domain K+ channels[END_REF]. A scrutiny on every subunit of K2P channels is beyond the scope of this review. Although there is not conclusive document about these channels expression in axons extruded in hypothalamic area and hypothalamic neurons in MS patients, their expression is main factor impacting the thermal sensitivity of neurons. These channels are not voltage-gated, since the absence of canonical voltage sensor domain [START_REF] Braun | Two-pore domain potassium channels: variation on a structural theme[END_REF][START_REF] Medhurst | Distribution analysis of human two pore domain potassium channels in tissues of the central nervous system and periphery[END_REF][START_REF] Wechselberger | Ionic channels and conductancebased models for hypothalamic neuronal thermosensitivity[END_REF]. In this context, their activity is influenced by physical and chemical stimuli, including mechanical and heat stresses [START_REF] Braun | Two-pore domain potassium channels: variation on a structural theme[END_REF]. Peripheral and central hyperthermia activate K2P channels, causing the outward flow of potassium ions from neurons and resulting in neuronal hyperpolarization and decreased action potential propagation [START_REF] Griffin | Temperature effects on membrane potential and input resistance in rat hypothalamic neurones[END_REF][START_REF] Wechselberger | Ionic channels and conductancebased models for hypothalamic neuronal thermosensitivity[END_REF]. Notably, the higher expression of K2P channels on thermal-sensitive neurons, the higher potassium leak current and the lower firing rate of action potentials. In accordance with their extensive expression in brain, potassium channels may be selective candidate in increased thermal sensitivity. In any case, the expression changes of potassium channels in afferent peripheral and central neurons and their role in altering thermal sensitivity of MS patients should be precisely investigated by future studies. C) Hypothalamic lesion-induced impairments in sympathetic outflows and the destruction of sudomotor pathways reduces sweating and consequently increases body temperature [START_REF] Haensch | Autonomic dysfunction in multiple sclerosis[END_REF][START_REF] Huang | Autonomic dysfunction in multiple sclerosis: implications for exercise[END_REF][START_REF] Keller | Reduced spontaneous sympathetic nerve activity in multiple sclerosis patients[END_REF]. D) There is decreased sweat output per gland [START_REF] Davis | Pilocarpineinduced sweat gland function in individuals with multiple sclerosis[END_REF].

E) The reduced current available to excite node of Ranvier results in a blockade in neuronal conduction [START_REF] Allen | Thermoregulatory Dysfunction in Multiple Sclerosis[END_REF][START_REF] Davis | Thermoregulatory dysfunction in multiple sclerosis[END_REF]Davis et al., 2010b). F) Other factors that could reduce conduction speed in demyelinated fibers include vasoconstriction and humoral factors [START_REF] Syndulko | Effects of temperature in multiple sclerosis: a review of the literature[END_REF]. Fatigue, which is associated with heat stress and which occurs in approximately 70% of individuals with MS individuals [START_REF] Krupp | Fatigue in multiple sclerosis[END_REF][START_REF] Krupp | Fatigue in multiple sclerosis, Multiple Sclerosis Therapeutics[END_REF][START_REF] Marino | Heat reactions in multiple sclerosis: an overlooked paradigm in the study of comparative fatigue[END_REF][START_REF] Martin | Reduced voluntary activation of human skeletal muscle during shortening and lengthening contractions in whole body hyperthermia[END_REF][START_REF] Nybo | Hyperthermia and central fatigue during prolonged exercise in humans[END_REF], can result from demyelinated lesions that lower central motor conduction and cortical excitability [START_REF] Humm | Quantification of Uhthoff's phenomenon in multiple sclerosis: a magnetic stimulation study[END_REF][START_REF] Petajan | Motor-evoked potentials in response to fatiguing grip exercise in multiple sclerosis patients[END_REF][START_REF] Sheean | An electrophysiological study of the mechanism of fatigue in multiple sclerosis[END_REF][START_REF] White | Effect of Increased Core Temperature on Cortical Excitability and Fatigue in Multiple Sclerosis Patients: 1786Board# 139 May 29 9: 00 AM-10: 30 AM[END_REF]. There is evidence that patients with advanced MS pathology likely have more failures in impulse conduction [START_REF] Smith | The pathophysiology of multiple sclerosis⋮ the mechanisms underlying the production of symptoms and the natural history of the disease[END_REF].

The ability to sense changes in skin temperature drives behavioral responses to heat stress (e.g., decreased physical work, removing clothes, seeking shade, etc.) and can also influence autonomic thermoregulation [START_REF] Davis | Thermoregulatory dysfunction in multiple sclerosis[END_REF]Davis et al., 2010b;[START_REF] Huang | Autonomic dysfunction in multiple sclerosis: implications for exercise[END_REF][START_REF] Huang | Thermoregulatory dysfunction in multiple sclerosis patients during moderate exercise in a thermoneutral environment (1104.17)[END_REF]. Studies by Filingere and colleagues [START_REF] Davis | Pilocarpineinduced sweat gland function in individuals with multiple sclerosis[END_REF] that used heat sensitivity of skin afferents using exercise as a heat stressor, and also by exposing them to a cold environment, indicated that cold sensitivity is decreased in patients with MS, suggesting that MS pathophysiology independently modulates afferent thermosensory function. Reduced coldinduced conduction speed in nerve fibers is greatest in A fibers, followed by B fibers and less so in C fibers [START_REF] Syndulko | Effects of temperature in multiple sclerosis: a review of the literature[END_REF]. This divergence in susceptibility to cold block may be related to nerve characteristics such as myelination, diameter, and threshold characteristics. This is supported by findings that nerve fibers, especially A fibers which have lower thresholds, faster conduction, greater myelination and diameters, have greater sensitivity to cold block [START_REF] Douglas | The effect of localized cooling on conduction in cat nerves[END_REF][START_REF] Todd | Anatomy of primary afferents and projection neurones in the rat spinal dorsal horn with particular emphasis on substance P and the neurokinin 1 receptor[END_REF]. Several studies suggest that contrary to expectations, the conduction velocity in sensory nerve fibers is increased by higher limb temperatures [START_REF] Franssen | The influence of temperature on nerve conduction in patients with chronic axonal polyneuropathy[END_REF][START_REF] Franssen | Nerve conduction and temperature: necessary warming time[END_REF][START_REF] Tavee | Nerve conduction studies: basic concepts[END_REF]. Body temperature fluctuations in patients with MS with infectious conditions, such as during the COVID-19 pandemic, could be exacerbated since there is a limited ability to mount counteracting febrile responses in these patients (Davis et al., 2010b). Although the majority of COVID-19 patients are asymptomatic, many others manifest some serious clinical symptoms [START_REF] Schneider | Covid-19 in outpatients-Is fever a useful indicator for SARS-CoV-2 infection?[END_REF][START_REF] Wölfel | Virological assessment of hospitalized patients with COVID-2019[END_REF]. Fever occurs initially in more than 50% of patients affected with COVID-19 [START_REF] Hui | Severe acute respiratory syndrome: historical, epidemiologic, and clinical features[END_REF][START_REF] Islam | Prevalence and characteristics of fever in adult and paediatric patients with coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis of 17515 patients[END_REF][START_REF] Qiu | Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study[END_REF]. Instant diagnosis of infection can prevent its transmission or to initiate countermeasures or successful confinements [START_REF] Schneider | Covid-19 in outpatients-Is fever a useful indicator for SARS-CoV-2 infection?[END_REF]. Although assessing fever may not be efficacious in all COVID-19 patients, it is however critical in individuals with pre-existing thermal dysregulation such as in patients with MS [START_REF] Racke | Multiple sclerosis and COVID-19: a great opportunity for databases promoting research and collaboration[END_REF][START_REF] Schneider | Covid-19 in outpatients-Is fever a useful indicator for SARS-CoV-2 infection?[END_REF]. Individuals with MS are at higher risk during the COVID-19 pandemic, as they often are treated with immunosuppressing drugs (IMDs) [START_REF] Hughes | COVID-19 in persons with multiple sclerosis treated with ocrelizumab-a pharmacovigilance case series[END_REF][START_REF] Loonstra | COVID-19 in multiple sclerosis: the Dutch experience[END_REF][START_REF] Louapre | Clinical characteristics and outcomes in patients with coronavirus disease 2019 and multiple sclerosis[END_REF][START_REF] Maghzi | COVID-19 in teriflunomide-treated patients with multiple sclerosis[END_REF][START_REF] Willis | Multiple sclerosis and the risk of infection: considerations in the threat of the novel coronavirus, COVID-19/SARS-CoV-2[END_REF]. Importantly, both diseases (MS and COVID-19) share the ability to induce febrile responses characteristic of cytokine storms [START_REF] Berger | COVID-19 and MS disease-modifying therapies[END_REF][START_REF] García | Immune response, inflammation, and the clinical spectrum of COVID-19[END_REF][START_REF] Sorenson | Dysregulation of cytokine pathways in chronic fatigue syndrome and multiple sclerosis[END_REF][START_REF] Zheng | Multiple sclerosis disease-modifying therapy and the COVID-19 pandemic: implications on the risk of infection and future vaccination[END_REF].

Fever is part of defensive responses of multicellular organisms (host) to invasion of microorganisms such as viruses, including SARS-CoV-2 [START_REF] Ogoina | Fever, fever patterns and diseases called 'fever'-a review[END_REF]. The febrile response includes endocrine, neurological and immunological mechanisms [START_REF] Dinarello | Fever and hyperthermia[END_REF][START_REF] Mackowiak | Temperature Regulation and the Pathogenesis of Fever In[END_REF]. SARS-CoV-2, as an exogenous pyrogen, can initiate the febrile responses through humoral and neuronal pathways [START_REF] Ogoina | Fever, fever patterns and diseases called 'fever'-a review[END_REF]. Upon entering the circulation, the virus then activates pathogen-associated molecular patterns (PAMPs) or pyrogenic cytokines [proinflammatory cytokines, namely, tumor necrosis factor-alpha (TNF-α), IL-1] [START_REF] Conti | Cytokines and fever[END_REF][START_REF] Jiang | Exposure to febrile temperature upregulates expression of pyrogenic cytokines in endotoxinchallenged mice[END_REF][START_REF] Romanovsky | Cells that trigger fever[END_REF]Steiner et al., 2006a;[START_REF] Turrin | Unraveling the molecular details involved in the intimate link between the immune and neuroendocrine systems[END_REF]. The circulatory microorganism's PAMPs and cytokines (released by host) activate toll-like receptors and cytokine receptors, respectively, on capillaries and also on the blood-brain barrier (BBB), leading to the release of prostaglandin E 2 (PGE 2 ) [START_REF] Conti | Cytokines and fever[END_REF][START_REF] Romanovsky | Cells that trigger fever[END_REF]Steiner et al., 2006a;[START_REF] Turrin | Unraveling the molecular details involved in the intimate link between the immune and neuroendocrine systems[END_REF]. PGE 2 binds to EP2 receptors in the preoptic area to activate thermal neurons in the anterior hypothalamus and reset the thermal balance point to a higher set-point [START_REF] Mackowiak | Temperature Regulation and the Pathogenesis of Fever In[END_REF][START_REF] Romanovsky | Cells that trigger fever[END_REF]Steiner et al., 2006a;[START_REF] Turrin | Unraveling the molecular details involved in the intimate link between the immune and neuroendocrine systems[END_REF]. It has been argued that the initial phase of the febrile response is dependent on PGE 2 synthetized in the liver and lungs prior to migrating to the brain, while the later phase of the febrile response is due to centrally synthetized PGE 2 [START_REF] Gross | Anatomy of a Fever[END_REF]Steiner et al., 2006b). Thus, exogenous pyrogens (such as SARS-CoV-2) are converted to endogenous pyrogens (PAMPs, cytokines) after entering the body. SARS-CoV-2 has a tropism for brainstem centers of the autonomic nervous system, where the virus serves to transfer a fever signal from peripheral nerves (such as the olfactory pathway) transfers to the hypothalamus, thalamus, and brainstem [START_REF] Blatteis | The onset of fever: new insights into its mechanism[END_REF][START_REF] Hopkins | Central nervous system recognition of peripheral inflammation: a neural, hormonal collaboration[END_REF][START_REF] Roth | Fever induction pathways: evidence from responses to systemic or local cytokine formation[END_REF][START_REF] Xu | Detection of severe acute respiratory syndrome coronavirus in the brain: potential role of the chemokine mig in pathogenesis[END_REF]. Much like fever produced by PGE 2 , exogenous pyrogen such as SARS-CoV-2 can activate pyrogenic cytokines, which in turn activate the hepatic branch of the vagal nerve and transfer the febrile signal to nerves in solitary and ambiguous nuclei [START_REF] Blatteis | The onset of fever: new insights into its mechanism[END_REF][START_REF] Li | The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients[END_REF][START_REF] Matsuda | The vagus nerve is one route of transneural invasion for intranasally inoculated influenza a virus in mice[END_REF][START_REF] Roth | Fever induction pathways: evidence from responses to systemic or local cytokine formation[END_REF][START_REF] Rummel | Localized vs. systemic inflammation in guinea pigs: a role for prostaglandins at distinct points of the fever induction pathways?[END_REF]. The signals from the solitary nucleus are delivered to preoptic and hypothalamic areas through the ventral noradrenergic bundle, resulting in norepinephrine release into these thermoregulatory areas [START_REF] Blatteis | The onset of fever: new insights into its mechanism[END_REF][START_REF] Roth | Fever induction pathways: evidence from responses to systemic or local cytokine formation[END_REF]. Norepinephrine mediates the vagal pathway by raising core temperature. The resetting of the thermal balance point to a higher set-point through these two humoral and neuronal signals initiates a feedback loop leading to early vasoconstriction and some clinical and behavioral manifestations to maintain body temperature. When there is no longer a fever signal in the CNS, the set-point then returns normal levels to activate heat loss mechanisms such as sweating [START_REF] Leggett | Approach to fever or suspected infection in the normal host[END_REF][START_REF] Mackowiak | Temperature Regulation and the Pathogenesis of Fever In[END_REF].

As discussed above, activation mechanisms to reduce core temperature are impaired in patients with MS. In addition, patients with MS have impairment in vascular function, likely related to reactive oxygen species (ROS)-induced oxidative stress [START_REF] Dhalla | Role of oxidative stress in cardiovascular diseases[END_REF][START_REF] Fjeldstad | Arterial compliance in multiple sclerosis: a pilot study[END_REF][START_REF] Ohl | Oxidative stress in multiple sclerosis: central and peripheral mode of action[END_REF][START_REF] Ranadive | Vascular dysfunction and physical activity in multiple sclerosis[END_REF]. Oxidative stress in patients with MS promotes viral replication [START_REF] Li | Roles of reactive oxygen species in cell signaling pathways and immune responses to viral infections[END_REF], while SARS-CoV-2 can impose a thermal burden through ROS production reduce nitric oxide (NO)-mediated vasodilation [START_REF] Ghosh | Missing pieces in the NF-κB puzzle[END_REF][START_REF] Xu | Molecular insights and therapeutic targets for diabetic endothelial dysfunction[END_REF][START_REF] Zhang | The role of inflammatory cytokines in endothelial dysfunction[END_REF]. In addition, MS and COVID-19 leads to inflammation and increased mitochondria-derived ROS production [START_REF] Alandijany | Mitochondrial dysfunction in rabies virus infection of neurons[END_REF]. ROS upregulate endothelial inflammasomes [especially, NLR family pyrin domain containing 3 (NLRP3)] and their signals, including caspase-1 and IL-1β in endothelial cells, thus initiating vascular pathology [START_REF] Long | ROS-induced NLRP3 inflammasome priming and activation mediate PCB 118-induced pyroptosis in endothelial cells[END_REF][START_REF] Martinon | The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β[END_REF].

High core temperature affects tissue metabolism, and can result in tissue necrosis, especially in neurons, and DNA unwinding [START_REF] Nagashima | Exercise and thermoregulation[END_REF]. The prevalence of MS can be three times higher than in men, and this can cause more severe symptoms because women have lower blood volumes, smaller heart sizes, a lower free fat mass, a higher percent of subcutaneous and whole fat, a higher body temperature threshold for dilating of cutaneous vessels, circadian changes in sex hormone levels that could lead to differences in body temperature regulation [START_REF] Mitchell | Acute response and chronic adaptation to exercise in women[END_REF].

Exercise improves thermoregulation

Homeothermic mechanisms cause intrinsic regulation of heat gain (metabolic production) and loss (sweat and evaporation) to maintain core body temperature set point [START_REF] Gisolfi | Hot Brain[END_REF][START_REF] Madden | Central nervous system circuits that control body temperature[END_REF][START_REF] Zalewski | Wholebody cryostimulation increases parasympathetic outflow and decreases core body temperature[END_REF]. Fluctuation from set point of body temperature stimulates hypothalamus to restore core temperature through changes in behaviors and physiological responses induced by the ANS [START_REF] Morrison | Central nervous system regulation of body temperature[END_REF]. Reductions and increases of core temperature trigger the activation of sympathetic efferent and cholinergic outflows, respectively. Adrenergic efferent release of norepinephrine to constrict cutaneous vessels, while cholinergic efferent secrete acetylcholine (Ach) to lower core temperature by vasodilation [START_REF] Flouris | Human behavioral thermoregulation during exercise in the heat[END_REF][START_REF] Gordon | Seven days of cold acclimation substantially reduces shivering intensity and increases nonshivering thermogenesis in adult humans[END_REF][START_REF] Morrison | Central mechanisms for thermoregulation[END_REF][START_REF] Tansey | Recent advances in thermoregulation[END_REF]. Maintenance of core body temperature is critical for work output and prevents premature fatigue [START_REF] Adams | Mild hypohydration impairs cycle ergometry performance in the heat: A blinded study[END_REF][START_REF] Fehling | Effect of exercise, heat stress and dehydration on myocardial performance[END_REF][START_REF] González-Alonso | Influence of body temperature on the development of fatigue during prolonged exercise in the heat[END_REF][START_REF] Sawka | Hydration effects on thermoregulation and performance in the heat[END_REF]. Physical exercise is a heat stressor that increases core body temperatures through increases in metabolism by exercising muscles [START_REF] Nadel | Tolerance to severe heat and exercise: Peripheral vascular responses to body fluid changes[END_REF][START_REF] Nadel | Mechanisms of thermal acclimation to exercise and heat[END_REF]. On the other hand, the adaptations induced by exercise training in cardiac output and stroke volume can mitigate this heat stress through facilitating heat transmission to the skin for cooling by evaporation, which is followed by a reduction in early fatigue [START_REF] Geor | Thermoregulatory adaptations associated with training and heat acclimation[END_REF][START_REF] Lim | Fundamental Concepts of Human Thermoregulation and Adaptation to Heat: A Review in the Context of Global Warming[END_REF]. Thus, improving body temperature regulation attenuates fatigue.

Although physical exercise acts as a heat stressor, regular exposure to this stressor promotes adaptations that limit its detrimental effects [START_REF] Périard | Cardiovascular adaptations supporting human exercise-heat acclimation[END_REF]. Although the increase in body temperature is probably a danger in MS patients, especially during or after an infection with corona virus, higher levels of heat stimulation are associated with greater adaptations in heat regulation [START_REF] Périard | Cardiovascular adaptations supporting human exercise-heat acclimation[END_REF]. These adaptations to exercise training are akin to the adaptions induced by exposure to heat [START_REF] Corbett | Adaptation to heat and exercise performance under cooler conditions: a new hot topic[END_REF][START_REF] Nielsen | Human circulatory and thermoregulatory adaptations with heat acclimation and exercise in a hot, dry environment[END_REF][START_REF] Weller | Quantification of the decay and reinduction of heat acclimation in dry-heat following 12 and 26 days without exposure to heat stress[END_REF].

Importantly, the probable adaptations acquired from exercise training that help to maintain core body temperature within a narrow range consist of neurophysiological adaptations, including cardiovascular, hematological, and hormonal changes, neural adaptations of the temperature set and thermoregulatory effectors, reduced production of metabolic heat by exercise, improved heat tolerance through the response to heat shock, and improved sweat economy (Figure 2) [START_REF] Nadel | Temperature regulation and prolonged exercise. Prolonged exercise[END_REF][START_REF] Nadel | Effect of hydration state of circulatory and thermal regulations[END_REF][START_REF] Takeda | Body temperature regulation during exercise and hyperthermia in diabetics[END_REF][START_REF] Werner | Temperature regulation during exercise: an overview[END_REF][START_REF] Yamauchi | Sweating economy by graded control in well-trained athletes[END_REF]. NO, nitric oxide; EDHF, endothelial-derived hyperpolarizing factor; VEGF, vascular endothelial growth factor; ROS, reactive oxygen species; APN, adiponectin.

The cardiovascular system regulates blood supply to exercising muscles to support their metabolism and also to the skin for dissipating the heat generated by exercising muscles [START_REF] Geor | Influence of training on exercise-associated heat tolerance in Thoroughbred horses[END_REF][START_REF] Rowell | Cardiovascular adjustments to thermal stress[END_REF]. Autonomic processes such as skin vasodilation and sweat production are compensatory procedures to maintain body temperature at a normal level [START_REF] Kenny | Restoration of thermoregulation after exercise[END_REF][START_REF] Nagashima | Exercise and thermoregulation[END_REF]. Exercise-induced hyperthermia impairs the function of ANS, which is measurable by heart rate variability and lasts > 80 min after the exercise session [START_REF] Armstrong | Heart rate variability and baroreceptor sensitivity following exercise-induced hyperthermia in endurance trained men[END_REF]. Thus, other factors can restore body heat balance. The initial increase in skin blood flow during hyperthermia is primarily due to withdrawal of sympathetic vasoconstriction [START_REF] Mcnamara | Endothelial nitric oxide synthase mediates the nitric oxide component of reflex cutaneous vasodilatation during dynamic exercise in humans[END_REF][START_REF] Wong | Sensory nerves and nitric oxide contribute to reflex cutaneous vasodilation in humans[END_REF]. The 85-95% increase in cutaneous blood flow and increased sweating is mediated by cholinergic outflows from sympathetic nerves [START_REF] Wong | Sensory nerves and nitric oxide contribute to reflex cutaneous vasodilation in humans[END_REF]. Vasodilation and sweating is achieved by release of Ach from cholinergic terminals of sympathetic nerves and also by the co-release of other vasodilators [START_REF] Bennett | Evidence for a Role for Vasoactive Intestinal Peptide in Active Vasodilatation in the Cutaneous Vasculature of Humans[END_REF][START_REF] Dean | VIP/PACAP receptor mediation of cutaneous active vasodilation during heat stress in humans[END_REF][START_REF] Johnson | Thermoregulatory and thermal control in the human cutaneous circulation[END_REF][START_REF] Kellogg | Cutaneous active vasodilation in humans is mediated by cholinergic nerve cotransmission[END_REF][START_REF] Mccord | Prostanoids contribute to cutaneous active vasodilation in humans[END_REF][START_REF] Wong | Sensory nerves and nitric oxide contribute to reflex cutaneous vasodilation in humans[END_REF][START_REF] Wong | H1 but not H2 histamine receptor activation contributes to the rise in skin blood flow during whole body heating in humans[END_REF]. Vasoactive intestinal peptide (VIP) [START_REF] Bennett | Evidence for a Role for Vasoactive Intestinal Peptide in Active Vasodilatation in the Cutaneous Vasculature of Humans[END_REF][START_REF] Dean | VIP/PACAP receptor mediation of cutaneous active vasodilation during heat stress in humans[END_REF], pituitary adenylate cyclase-activating peptide (PACAP) [START_REF] Rambotti | PACAP activated adenylate cyclase in human sweat glands. An ultracytochemical study[END_REF][START_REF] Wallengren | Vasoactive peptides in the skin[END_REF][START_REF] Warren | Pituitary Adenylate Cyclase Activating Polypeptide is a Potent Vasodilator in Humans[END_REF], vitronectinderived peptide (VDP) [START_REF] Mccord | Prostanoids contribute to cutaneous active vasodilation in humans[END_REF], histamine [START_REF] Wong | H1 but not H2 histamine receptor activation contributes to the rise in skin blood flow during whole body heating in humans[END_REF], and substance-P [START_REF] Wong | Transient receptor potential vanilloid type 1 channels contribute to reflex cutaneous vasodilation in humans[END_REF][START_REF] Wong | Neurokinin-1 receptor desensitization attenuates cutaneous active vasodilatation in humans[END_REF] are co-released with Ach. These cotransmitters also increase the production of local NO [START_REF] Kellogg | Nitric oxide and receptors for VIP and PACAP in cutaneous active vasodilation during heat stress in humans[END_REF][START_REF] Klede | The effect of the nitric oxide synthase inhibitor N-nitro-L-arginine-methyl ester on neuropeptide-induced vasodilation and protein extravasation in human skin[END_REF][START_REF] Mccord | Prostanoids contribute to cutaneous active vasodilation in humans[END_REF][START_REF] Shibasaki | Acetylcholine released from cholinergic nerves contributes to cutaneous vasodilation during heat stress[END_REF][START_REF] Wilkins | Mechanisms of vasoactive intestinal peptide-mediated vasodilation in human skin[END_REF][START_REF] Wong | Sensory nerves and nitric oxide contribute to reflex cutaneous vasodilation in humans[END_REF][START_REF] Wong | Neurokinin-1 receptor desensitization to consecutive microdialysis infusions of substance P in human skin[END_REF][START_REF] Wong | H1 but not H2 histamine receptor activation contributes to the rise in skin blood flow during whole body heating in humans[END_REF]. For instance, substance-P activates Neurokinin-1 (NK1) receptors to increase NO levels [START_REF] Wong | Neurokinin-1 receptor desensitization attenuates cutaneous active vasodilatation in humans[END_REF]. However, substance-P also causes microvascular dilation by NO independent mechanisms by the degranulation of cutaneous mast cells, causing local increases in histamine levels [START_REF] Huttunen | Neuropeptide-and capsaicin-induced histamine release in skin monitored with the microdialysis technique[END_REF]. Increased cutaneous microvascular reactivity and function are positively related to VO 2 max [START_REF] Hodges | Influence of age, sex, and aerobic capacity on forearm and skin blood flow and vascular conductance[END_REF][START_REF] Middlebrooke | Does aerobic fitness influence microvascular function in healthy adults at risk of developing Type 2 diabetes?[END_REF][START_REF] Roche | Skin microvascular reactivity in children and adolescents with type 1 diabetes in relation to levels of physical activity and aerobic fitness[END_REF][START_REF] Tew | Effects of ageing and fitness on skin-microvessel vasodilator function in humans[END_REF].

Improvements in the thermoregulatory components produced by regular physical exercise, especially endurance/aerobic training, are related to increases in cardiac output and antioxidant enzyme levels [START_REF] Tew | Endurance exercise training enhances cutaneous microvascular reactivity in post-menopausal women[END_REF][START_REF] Tew | Effects of ageing and fitness on skin-microvessel vasodilator function in humans[END_REF], while increases in skin blood flow are due to increased plasma volume [START_REF] Ikegawa | Effects of hypohydration on thermoregulation during exercise before and after 5-day aerobic training in a warm environment in young men[END_REF]. Aerobic exercise training for 6-10 days increases the plasma volume [START_REF] Convertino | Blood volume: its adaptation to endurance training[END_REF][START_REF] Costill | Exercise induced sodium conservation: changes in plasma renin and aldosterone[END_REF][START_REF] Fellmann | Hormonal and plasma volume alterations following endurance exercise[END_REF][START_REF] Williams | Effect of the exercise of seven consecutive days hill-walking on fluid homeostasis[END_REF], due to increased intravascular protein (albumin) by triggering the production of hepatic albumin and reuptake of electrolytes (sodium) [START_REF] Convertino | Role of thermal and exercise factors in the mechanism of hypervolemia[END_REF][START_REF] Convertino | Blood volume: its adaptation to endurance training[END_REF][START_REF] Fellmann | Hormonal and plasma volume alterations following endurance exercise[END_REF][START_REF] Nadel | Importance of albumin in the plasma volume expansion process[END_REF], increases in hormones that regulate fluid volume (e.g., aldosterone, arginine vasopressin, natriuretic atrial peptide (NAP) and renin-angiotensin) [START_REF] Convertino | Role of thermal and exercise factors in the mechanism of hypervolemia[END_REF][START_REF] Fellmann | Hormonal and plasma volume alterations following endurance exercise[END_REF][START_REF] Nagashima | Intense exercise stimulates albumin synthesis in the upright posture[END_REF][START_REF] Wade | Plasma aldosterone and renal function in runners during a 20-day road race[END_REF][START_REF] Yang | Albumin synthesis after intense intermittent exercise in human subjects[END_REF]. Higher blood volume increases blood pressure and this results in increased shear stress in the vasculature [START_REF] Birk | Effects of exercise intensity on flow mediated dilation in healthy humans[END_REF][START_REF] Laughlin | Importance of hemodynamic forces as signals for exercise-induced changes in endothelial cell phenotype[END_REF]. The increased heart rate during exercise stimulates contractility of heart rate by activation of the sympathetic nervous system, which also increases shear stress [START_REF] Blair | Vasomotor responses in the human arm during leg exercise[END_REF]. These local hemodynamic changes activate endothelial mechanical-sensitive ion channels such as piezo1 channels and G-proteins, caveolin, and integrins. Mechanical signals lead to calcium entering, activation of endothelial nitric oxide synthase (eNOS) and the production of NO and endothelial-derived hyperpolarizing factor (EDHF) [START_REF] Awolesi | Cyclic strain increases endothelial nitric oxide synthase activity[END_REF][START_REF] Caolo | Shear stress activates ADAM10 sheddase to regulate Notch1 via the Piezo1 force sensor in endothelial cells[END_REF][START_REF] Green | Effect of exercise training on endotheliumderived nitric oxide function in humans[END_REF][START_REF] Laughlin | Importance of hemodynamic forces as signals for exercise-induced changes in endothelial cell phenotype[END_REF][START_REF] Silva | Physical exercise, β-adrenergic receptors, and vascular response[END_REF]. NO contributes to approximately 30% increases in responses of cutaneous blood flow to Ach released during physical exercise [START_REF] Boutsiouki | Recovery of nitric oxide from acetylcholine-mediated vasodilatation in human skin in vivo[END_REF][START_REF] Holowatz | Mechanisms of acetylcholinemediated vasodilatation in young and aged human skin[END_REF][START_REF] Kellogg | Acetylcholine-induced vasodilation is mediated by nitric oxide and prostaglandins in human skin[END_REF][START_REF] Laughlin | Importance of hemodynamic forces as signals for exercise-induced changes in endothelial cell phenotype[END_REF]. For better regulation of core temperature, NO and hypoxia resulting from exercise can upregulate vascular endothelial growth factor (VEGF), which promotes microvascular numbers (angiogenesis) and increases capillary density that promotes cutaneous perfusion [START_REF] Breen | Skeletal muscle capillarity during hypoxia: VEGF and its activation[END_REF][START_REF] Jensen | Effect of high intensity training on capillarization and presence of angiogenic factors in human skeletal muscle[END_REF][START_REF] Lloyd | VEGF receptor antagonism blocks arteriogenesis, but only partially inhibits angiogenesis, in skeletal muscle of exercise-trained rats[END_REF][START_REF] Michiels | Endothelial cell responses to hypoxia: initiation of a cascade of cellular interactions[END_REF].

The optimization of vascular structure and improved blood flow distribution can attenuate some of the heat strain produced by coronavirus disease in patients with neurological disorders.

Increases in antioxidant enzyme levels induced by exercise also assists in promoting skin vasodilation by improving NO bioavailability and reducing damage of lipid peroxidationmediated damage of vascular endothelial cells [START_REF] Dawson | Effects of acute exercise on flowmediated dilatation in healthy humans[END_REF][START_REF] Eskurza | Effect of acute and chronic ascorbic acid on flow-mediated dilatation with sedentary and physically active human ageing[END_REF][START_REF] Finaud | Oxidative stress[END_REF][START_REF] Holowatz | Acute ascorbate supplementation alone or combined with arginase inhibition augments reflex cutaneous vasodilation in aged human skin[END_REF][START_REF] Leeuwenburgh | Oxidative stress and antioxidants in exercise[END_REF][START_REF] Tew | Endurance exercise training enhances cutaneous microvascular reactivity in post-menopausal women[END_REF][START_REF] Violi | Nitric oxide and its role in lipid peroxidation[END_REF]. Chronic aerobic exercise increases the activity of vasodilatory mediators such as NO, prostacyclin, prostaglandins, bradykinin, and EDHF that promotes cutaneous perfusion and limits exercise-induced increases of core temperature [START_REF] Colberg | Exercise status affects skin perfusion via prostaglandin, nitric oxide, and EDHF pathways in diabetes[END_REF][START_REF] Colberg | Chronic exercise is associated with enhanced cutaneous blood flow in type 2 diabetes[END_REF][START_REF] Gooding | Maximum skin hyperaemia induced by local heating: possible mechanisms[END_REF][START_REF] Lenasi | The effect of nitric oxide synthase and cyclooxygenase inhibition on cutaneous microvascular reactivity[END_REF][START_REF] Sokolnicki | of nitric oxide to cutaneous microvascular dilation in individuals with type 2 diabetes mellitus[END_REF][START_REF] Wang | Effects of exercise training and detraining on cutaneous microvascular function in man: the regulatory role of endothelium-dependent dilation in skin vasculature[END_REF]. In addition, these factors interact to enhance skin perfusion by increasing cutaneous flow produced by Ach [START_REF] Gaubert | Endotheliumderived hyperpolarizing factor as an in vivo back-up mechanism in the cutaneous microcirculation in old mice[END_REF][START_REF] Lenasi | Effect of regular physical training on cutaneous microvascular reactivity[END_REF][START_REF] Medow | Nitric oxide and prostaglandin inhibition during acetylcholine-mediated cutaneous vasodilation in humans[END_REF][START_REF] Padilla | Vascular effects of exercise: endothelial adaptations beyond active muscle beds[END_REF][START_REF] Wang | Effects of exercise training and detraining on cutaneous microvascular function in man: the regulatory role of endothelium-dependent dilation in skin vasculature[END_REF]. Increased insulin-induced tissue metabolism improves endothelial function induced by aerobic exercise by phosphorylating eNOS and increasing NO production [START_REF] Ghafouri | Enhancement of insulin-induced cutaneous vasorelaxation by exercise in rats: A role for nitric oxide and KCa2+ channels[END_REF][START_REF] Harris | Increased nitric oxide synthase activity and Hsp90 association in skeletal muscle following chronic exercise[END_REF][START_REF] Kashyap | Insulin resistance is associated with impaired nitric oxide synthase activity in skeletal muscle of type 2 diabetic subjects[END_REF][START_REF] Rossi | Effect of chronic aerobic exercise on cutaneous microcirculatory flow response to insulin iontophoresis and to ischemia in elderly males[END_REF], which activates Ca 2+ -activated potassium (K + ) channels [START_REF] Bychkov | Calcium-activated potassium channels and nitrate-induced vasodilation in human coronary arteries[END_REF][START_REF] Kane | ATP-sensitive K+ channel knockout compromises the metabolic benefit of exercise training, resulting in cardiac deficits[END_REF][START_REF] Merkus | KCa+ channels contribute to exercise-induced coronary vasodilation in swine[END_REF][START_REF] Misurski | Insulin-induced biphasic responses in rat mesenteric vascular bed: role of endothelin[END_REF] and ATP-sensitive K + channels [START_REF] Mckay | Role of nitric oxide, adenosine, and ATP-sensitive potassium channels in insulin-induced vasodilation[END_REF].

Exercise and endurance training change body composition (reduce subcutaneous body fat), serum lipid and lipoproteins (increases high-density lipoprotein cholesterol [HDL-C]), and attenuates the oxidation of low-density lipoprotein cholesterol (LDL-C) [START_REF] Gordon | The effects of exercise training on the traditional lipid profile and beyond[END_REF][START_REF] Kodama | Effect of aerobic exercise training on serum levels of high-density lipoprotein cholesterol: a meta-analysis[END_REF][START_REF] Kraus | Effects of the amount and intensity of exercise on plasma lipoproteins[END_REF][START_REF] Neves | Effect of body fat and gender on body temperature distribution[END_REF]. Oxidation of LDL-C inhibits the release of NO and mitigates endothelium-dependent vasodilation [START_REF] Liao | Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase[END_REF]. Exercise increases the expression of antioxidant enzymes such as superoxide dismutase (SOD), which increases the bioavailability of NO inhibition of LDL-C oxidation and enhances the vasodilatory sensitivity to chronic activation of β-adrenergic receptors on microvascular walls [START_REF] Woodman | Endurance exercise training improves endothelium-dependent relaxation in brachial arteries from hypercholesterolemic male pigs[END_REF][START_REF] Woodman | Exercise attenuates the effects of hypercholesterolemia on endothelium-dependent relaxation in coronary arteries from adult female pigs[END_REF].

Plasma levels of adiponectin (APN) are increased by regular physical exercise (Saeidi et al., 2020;Zouhal et al. 2021). APN binds to adiponectin receptor 1 (AdipR1) in endothelial cells, mitigating the induction of inflammasomes, especially NLPR3, whose signals include activation of caspase-1 and IL-1β [START_REF] Du | Adiponectin at physiologically relevant concentrations enhances the vasorelaxative effect of acetylcholine via Cav-1/AdipoR-1 signaling[END_REF][START_REF] Hui | Adiponectin and cardiovascular health: an update[END_REF][START_REF] Lee | Vascular Protection by Exercise in Obesity: Inflammasome-associated Mechanisms[END_REF][START_REF] Lee | Physical activity protects NLRP 3 inflammasome-associated coronary vascular dysfunction in obese mice[END_REF][START_REF] Lee | Exercise training improves endothelial function via adiponectin-dependent and independent pathways in type 2 diabetic mice[END_REF]. Downregulated inflammasomes attenuate ROS production in endothelial cells. Therefore, exercise training increases endothelial APN levels to promote NO production and its bioavailability, and reduces oxidative and apoptotic damage of microvessels [START_REF] Chen | Adiponectin stimulates production of nitric oxide in vascular endothelial cells[END_REF][START_REF] Gleeson | The antiinflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease[END_REF][START_REF] Moien-Afshari | Exercise restores endothelial function independently of weight loss or hyperglycaemic status in db/db mice[END_REF][START_REF] Plant | Adiponectin attenuates endothelial dysfunction induced by oxidised low-density lipoproteins[END_REF][START_REF] Wang | Adiponectin inhibits NLRP3 inflammasome by modulating the AMPK-ROS pathway[END_REF][START_REF] Zhang | Coronary endothelial dysfunction induced by nucleotide oligomerization domain-like receptor protein with pyrin domain containing 3 inflammasome activation during hypercholesterolemia: beyond inflammation[END_REF].

Engaging in regular physical exercise leads to adaptations in the cardiovascular system and skeletal muscles, whereby less metabolic exertion is required to perform the same intensity of exercise [START_REF] James | Shortterm heat acclimation improves the determinants of endurance performance and 5-km running performance in the heat[END_REF]Lorenzo et al., 2010;[START_REF] Nadel | Mechanisms of thermal acclimation to exercise and heat[END_REF][START_REF] Pivarnik | Effect of endurance training and heat acclimation on aerobic capacity, blood volume and plasma testosterone[END_REF][START_REF] Sawka | Influence of heat stress and acclimation on maximal aerobic power[END_REF]. Exercise reduces vascular inflammation [START_REF] Pedersen | The diseasome of physical inactivity-and the role of myokines in muscle-fat cross talk[END_REF][START_REF] Ribeiro | Is exercise training an effective therapy targeting endothelial dysfunction and vascular wall inflammation[END_REF], for example by releasing IL-6 (a myokine released by skeletal muscles into the circulation during physical exercise) [START_REF] Jankord | Sex difference in link between interleukin-6 and stress[END_REF][START_REF] Pedersen | The diseasome of physical inactivity-and the role of myokines in muscle-fat cross talk[END_REF][START_REF] Pedersen | Muscle as an endocrine organ: focus on muscle-derived interleukin-6[END_REF][START_REF] Pedersen | The metabolic role of IL-6 produced during exercise: is IL-6 an exercise factor[END_REF][START_REF] Suzuki | Characterization and modulation of systemic inflammatory response to exhaustive exercise in relation to oxidative stress[END_REF] to increase anti-inflammatory (IL-10, IL-1ra) and lower proinflammatory (TNF-α, IL-1β) cytokine levels [START_REF] Pedersen | The diseasome of physical inactivity-and the role of myokines in muscle-fat cross talk[END_REF][START_REF] Shephard | Cytokine responses to physical activity, with particular reference to IL-6: sources, actions, and clinical implications[END_REF][START_REF] Starkie | Exercise and IL-6 infusion inhibit endotoxin-induced TNF-α production in humans[END_REF][START_REF] Suzuki | Characterization of exercise-induced cytokine release, the impacts on the body, the mechanisms and modulations[END_REF].

Other mechanisms related to the beneficial effects of exercise in reducing core temperature includes the release of ATP by endothelial cells and erythrocytes [START_REF] Ellsworth | Regulation of blood flow distribution in skeletal muscle: role of erythrocyte-released ATP[END_REF][START_REF] Hellsten | Adenosine concentrations in the interstitium of resting and contracting human skeletal muscle[END_REF][START_REF] Hellsten | Vasodilator interactions in skeletal muscle blood flow regulation[END_REF][START_REF] Singel | Chemical physiology of blood flow regulation by red blood cells: the role of nitric oxide and S-nitrosohemoglobin[END_REF]. ATP, which is released during exercise and in response to hypoxia and shear stress, binds to P2Y receptors in microvessels to release NO and PGs (prostacyclin, PGE 2 ) [START_REF] Burnstock | Purinergic signalling in the musculoskeletal system[END_REF][START_REF] Corr | Analysis of P2-purinoceptor subtypes on the smooth muscle and endothelium of rabbit coronary artery[END_REF][START_REF] Frandsen | Inhibition of nitric oxide synthesis by systemic NG-monomethyl-L-arginine administration in humans: effects on interstitial adenosine, prostacyclin and potassium concentrations in resting and contracting skeletal muscle[END_REF][START_REF] Hellsten | Adenosine concentrations in the interstitium of resting and contracting human skeletal muscle[END_REF][START_REF] Huang | Shear Stress-Induced Release of Prostaglandin H2 in Arterioles of Hypertensive Rats[END_REF]Mortensen et al., 2009a;Mortensen et al., 2009b;Nyberg, Michael et al., 2013) and hyperpolarization of vascular cells [START_REF] Crecelius | ATP-mediated vasodilatation occurs via activation of inwardly rectifying potassium channels in humans[END_REF][START_REF] Rosenmeier | Activation of ATP/UTP-selective receptors increases blood flow and blunts sympathetic vasoconstriction in human skeletal muscle[END_REF]. Additionally, increased concentrations of plasma ATP during exercise inhibits sympathetic vasoconstriction of α-adrenergic receptors, a phenomenon known as functional sympatholysis [START_REF] Kirby | Graded sympatholytic effect of exogenous ATP on postjunctional α-adrenergic vasoconstriction in the human forearm: implications for vascular control in contracting muscle[END_REF][START_REF] Rosenmeier | Circulating ATP-induced vasodilatation overrides sympathetic vasoconstrictor activity in human skeletal muscle[END_REF].

Exercise, especially endurance training, attenuates the effects of endothelial-dependent vasoconstriction produced by endothelin-1 [START_REF] Beck | Exercise training improves endothelial function in young prehypertensives[END_REF][START_REF] Maeda | Aerobic exercise training reduces plasma endothelin-1 concentration in older women[END_REF]Nyberg, M et al., 2013;[START_REF] Nyberg | Biomarkers of vascular function in premenopausal and recent postmenopausal women of similar age: effect of exercise training[END_REF], thromboxane A 2 [START_REF] Hansen | Exercise training alters the balance between vasoactive compounds in skeletal muscle of individuals with essential hypertension[END_REF][START_REF] Stergioulas | Effects of physical conditioning on lipids and arachidonic acid metabolites in untrained boys: a longitudinal study[END_REF], and angiotensin II [START_REF] Rush | Vascular biology of angiotensin and the impact of physical activity[END_REF][START_REF] Zucker | Modulation of angiotensin II signaling following exercise training in heart failure[END_REF]. Adaptations in sweat rates may be important when monitoring body core temperature. Changes in response to exercise include increases in cholinergic sensitivity, greater rate and efficiency of eccrine glands in sweat production per gland, increased number and sensitivity of muscarinic receptors responsible for sweating, and reduced choline esterase activity (Lorenzo and Minson, 2010;[START_REF] Périard | Cardiovascular adaptations supporting human exercise-heat acclimation[END_REF]. Thus, exercise training can reduce the threshold for initiating cutaneous blood flow and sweat production in response to increases in core body temperature.

The majority of the vascular benefits produced by exercise training occur via increased NO bioavailability. Exercise-induced increases in NO inhibits virus replication by suppressing ribonucleotide reductase [START_REF] Ellermann-Eriksen | Macrophages and cytokines in the early defence against herpes simplex virus[END_REF][START_REF] Komatsu | Mechanisms of cytokine-mediated inhibition of viral replication[END_REF], and is supported by findings that NOS-deficient mice are more susceptible to viral infections [START_REF] Gamba | Early inhibition of nitric oxide production increases HSV-1 intranasal infection[END_REF][START_REF] Maclean | Mice lacking inducible nitric-oxide synthase are more susceptible to herpes simplex virus infection despite enhanced Th1 cell responses[END_REF].

Exercise-induced adaptations in thermoregulation occur within 3-14 days [START_REF] Garrett | Induction and decay of short-term heat acclimation in moderately and highly trained athletes[END_REF], with the initial changes in the cardiovascular system associated with hypervolemia (Lorenzo et al., 2010;[START_REF] Nielsen | Human circulatory and thermoregulatory adaptations with heat acclimation and exercise in a hot, dry environment[END_REF][START_REF] Shvartz | Heat acclimation, physical fitness, and responses to exercise in temperate and hot environments[END_REF][START_REF] Weller | Quantification of the decay and reinduction of heat acclimation in dry-heat following 12 and 26 days without exposure to heat stress[END_REF] and secondary adaptations related to sweat production [START_REF] Nielsen | Human circulatory and thermoregulatory adaptations with heat acclimation and exercise in a hot, dry environment[END_REF][START_REF] Roberts | Skin blood flow and sweating changes following exercise training and heat acclimation[END_REF][START_REF] Shvartz | Heat acclimation, physical fitness, and responses to exercise in temperate and hot environments[END_REF][START_REF] Wyndham | Acclimization in a hot, humid environment: cardiovascular adjustments[END_REF]. Light to moderate-intensity endurance training (≥ 50% VO 2 max) for at least one week optimal to stimulate these adaptations and restore body temperature to healthy levels (Lorenzo et al., 2010;[START_REF] Périard | Adaptations and mechanisms of human heat acclimation: applications for competitive athletes and sports[END_REF][START_REF] Sawka | Influence of heat stress and acclimation on maximal aerobic power[END_REF]. Furthermore, thermobalance during steady-state exercise occurs within 30-45 min and increases in body temperature occur within 15-20 min of physical exercise [START_REF] Kenny | Thermometry, calorimetry, and mean body temperature during heat stress[END_REF]. Thus, exercise of at least 20 min is needed to promote thermoregulatory adaptations. Since MS patients are very sensitive to heat stress, with exacerbating clinical signs during and after infection with SARS-CoV-2 [START_REF] Willis | Multiple sclerosis and the risk of infection: considerations in the threat of the novel coronavirus, COVID-19/SARS-CoV-2[END_REF], management of the risks associated with heat stress should include physical exercise using exercise/rest (intermittent exercise) protocols), with close monitoring of hydration and cool-down strategies.

Conclusions

We reviewed thermoregulation management following exercise training in MS patients infected with COVID-19. The mechanisms of exercise-induced vascular benefits involve increased eNOS bioavailability and the anti-inflammatory effects of NO. Regular physical exercise increases vasodilation sensitivity to maintain core body temperature by reducing the sweat threshold and increasing responses of cutaneous vessels. Exercise-induced adaptations in the cardiovascular system mitigates perceived exertion and fatigue during physical exercise through improved thermoregulation, allowing MS patients to better manage neurological signs during and after infection with SARS-CoV-2.

Figure. 1 .

 1 Figure. 1. Schematic representation of dysfunctional pathways of thermoregulation in individuals with MS disease and the exacerbating role of COVID-19 in increasing heat strain. MS, multiple sclerosis; COVID-19, coronavirus disease-2019; ANS, autonomic nervous system; ROS, reactive oxygen species; NO, nitric oxide; PAMPs, pathogen-associated molecular patterns; TLRs, toll-like receptors; PGE 2 , prostaglandin E 2 .

Figure. 2 .

 2 Figure. 2. Schematic diagram of physical exercise-induced adaptations in improving thermal management. The green rectangles represent the main adaptations induced directly by regular physical exercise that are associated with secondary adaptations (in black rectangles). The bold arrows show the main adaptations; oval circles indicate increased cutaneous blood flow resulting from vascular adaptations. Na + , sodium; NAP, natriuretic atrial peptide; VIP, vasoactive intestinal peptide; PACAP, pituitary adenylate cyclase-activating polypeptide; VDP, vasculardilating prostanoids; TRPV-1, transient receptor potential vanilloid type 1; NK-1, neurokinin-1;

Author Contributions

OR, BT, NZ and HZ conceptualized and wrote the first draft. AMT, IL, HZ, and OR developed the study concept. KG, KS, and HZ reviewed and edited the final version of manuscript. All authors contributed to the article and approved the submitted version.

Conflicts of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.