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DOI: 10.1055/a-1720-0369
Type and Intensity as Key Variable of Exercise in Metainflammation Diseases: A Review
- Abstract
- Introduction
- Type of exercise and intensity as key variable on monocytes and lymphocytes morpho-functional changes: Does it really matter?
- Monocytes and lymphocytes physical exercise-induced morpho-functional changes in metabolic diseases
- Future perspectives and conclusion
- References
Abstract
Monocyte and lymphocyte subpopulations exhibit functions that vary between the anti- and pro-inflammatory spectrum, such as classic CD16- and non-classical CD16+monocytes, as well as T helper 2 lymphocytes (Th2), the Th1/Th17 lymphocytes ratio, and T regulatory lymphocytes (Treg). Metabolic disease-associated inflammation is accompanied by an imbalance in monocyte and lymphocyte phenotypes and functionality, as well as a stronger proportion of inflammatory subpopulations. These changes appear to be important for the development and progression of diseases like diabetes and cardiovascular disease. On the other hand, the regular practice of physical exercise is an important tool to restore the functionality of monocytes and lymphocytes, and to balance the subtypes ratio. However, key variables regarding exercise prescription, such as the type of exercise, intensity, and volume differentially impact on the acute and chronic immune response in individuals diagnosed with meta-inflammation diseases. Here, we discuss the impact of different physical exercise protocols, acutely and chronically, on monocytes and lymphocytes of individuals with metabolic disease-associated inflammation. In this review, we focus on the best effects of different exercise protocols to dose the “exercise pill” in different inflammatory status.
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Introduction
For decades it has been argued that obesity and physical inactivity are public, economic and clinical health problems [1]. The prevalence of obesity and physical inactivity has increased significantly worldwide [2], so that approximately half of the world’s population is obese and physically inactive [3]. In this scenario, a sedentary lifestyle, overnutrition, and an unhealthy diet are risk factors interrelated with several metabolic diseases, such as obesity, type 2 diabetes mellitus (T2DM) [4], dyslipidemia [5] and non-alcoholic liver disease [6]. From an economic and public health perspective, if around 10% of the world population became physically active, it would prevent around half a million deaths annually and save billions of dollars annually in health care expenses [2]. Thus, it is necessary to identify strategies and target mechanisms involved in metabolic disease-associated inflammation [1]. Therefore, the mechanisms that support metabolic abnormalities is crucial in this perspective review.
Sophisticated studies have shown that the excessive intake of nutrients, especially saturated fatty acids and glucose, results in metabolic impairment, compromising not only organs and tissues but also the functionality of immune cells and, consequently, upregulation of classical inflammatory pathways [7] [8] [9]. The perpetuation of this systemic and local inflammatory environment, marked by the hyperactivation of immune cells and release of pro-inflammatory cytokines, favors insulin resistance, glucose intolerance, and accumulation of ectopic fat [10] [11] [12]. Together, these characteristics are associated with an increase in inflammatory monocytes and lymphocytes in the bloodstream, as well as a higher proportion of pro-inflammatory macrophages (M1) in metabolically active peripheral tissues, mainly adipose, hepatic, and skeletal muscle tissue [13] [14] [15] [16] [17] [18] [19]. In order to mitigate this inflammatory scenario, the physical exercise is a non-pharmacological strategy to attenuate the metabolic and inflammatory disturbance.
The practice of regular physical exercise is well-known as a promising strategy to restore the anti-inflammatory profile and reestablish the concentrations and store of energetic substrates, favoring the increase in T regulatory lymphocytes (Tregs), CD16- monocytes, and anti-inflammatory macrophages (M2), and enhancing insulin sensitivity and reducing body fat [13] [20] [21] [22]. Although physical exercise induces these changes, which may prevent or even reduce the deleterious effects, of metabolic disease-associated inflammation, previous studies have indicated that the type and intensity of physical exercise may be a key variable to optimize the subpopulations and function of immune cells [23] [24]. Thus, knowledge about the alterations caused by intensity or type of exercise in monocytes and lymphocytes in individuals with metabolic diseases could favor the development of more appropriate treatment or prevention strategies. Therefore, the two main purposes of this perspective review are 1) to highlight the intensity and type of exercise, both acute and chronic, as key variables to provoke morphofunctional changes in monocytes and lymphocytes in metabolic disease-associated inflammation and 2) to elucidate the mechanisms proposed to be involved in the regulation of metabolic disease-associated inflammation induced by physical exercise.
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Type of exercise and intensity as key variable on monocytes and lymphocytes morpho-functional changes: Does it really matter?
Over the past few years, several studies have extensively investigated the effects of physical exercise and physical fitness status on changes in immune cells in different scenarios (health, metabolic diseases, and aging). The practice of different types of exercise – i. e., aerobic and strength exercise, different intensities, volumes, and schemes, has been the central discussion in guidelines to promote global improvement in health, such as musculoskeletal, neuro-endocrine-metabolic, and cardiovascular adaptations in individuals with metabolic diseases [25] [26]. However, a consensus on the effect of different exercise protocols – acutely and chronically, on systemic anti-inflammatory adaptations in individuals with metabolic diseases remains limited.
Acute exercise session and metainflammation diseases
It is well described that a single session of physical exercise induces changes in inflammatory markers, regardless of changes in body fat [27] [28] [29]. In addition, the changes found after an acute physical exercise session may support the understanding of long-term adaptations [30] [31] [32]. The literature includes few studies on the influence of a single session of physical exercise on the population of lymphocytes and monocytes ([Table 1]). We will highlight the main findings of the studies found below.
Design |
Exercise protocol |
Results |
Other information |
---|---|---|---|
Obesity, overweight and/or sedentary |
|||
Huang et al. (2019) [38] 2 groups (M)
|
|
|
|
Slusher et al. (2017) [33]2 groups (18 to 35 y)
|
|
|
|
Peres et al. (2020) [39] ]4 groups (M, 18 to 30)
|
|
|
|
Dorneles et al. (2019) [21]2 groups (M)
|
|
|
|
Nickel et al. (2012) [80]3 groups (M, 30 to 60 y)
|
|
|
|
Phillips et al. (2008) [45]4 groups (W, 64 to 72 y)
|
|
|
|
Bay et al. (2020) [51]5 groups (M and F, above 18 y)
|
|
|
|
Dorneles et al. (2020) [35] 2 groups (M, 24 to 32 y)
|
|
|
|
T2DM or insulin resistant |
|||
Durrer et al. (2017) [14]2 groups (no gender distribution reported).
|
|
|
|
McCormick et al. (2019) [58] 2 groups (27 to 61 y)
|
|
|
|
De Matos et al. (2016) [59]3 groups (18 to 55 y)
|
|
|
|
MetS |
|||
Wonner et al. (2018) [64] 3 groups
|
60 sec or until exhaustion of cycling at 400 W |
|
|
Note: MAV: maximum aerobic velocity, HIIE: high-intensity intermittent exercise, HRmax: heart rate maximum, VO2peak: peak oxygen consumption, RM: maximum repetition, CD: cluster differentiation, TBARS: thiobarbituric acid reactive substance, IGF-1: insulin-like growth factor-1, NF-κB: nuclear factor kappa B, H4Ac: histone H4 acetylation, LC3: light chain 3, Bax: B-cell lymphoma 2-associated X protein, Bcl-2: B-cell lymphoma 2, HOMA1-IR: homeostatic model assessment 1 of insulin resistance, PTX3: pentraxin 3, H2O2: hydrogen peroxide, GSH: glutathione, CRP: C-reactive protein, ROS: reactive oxygen species, CTLA-4: cytotoxic T lymphocyte antigen-4, SVC: stroma-vascular cell, MAP1LC3B: microtubule-associated protein 1 light chain 3 beta, p62/SQSTM1: sequestosome-1, ADA: adenosine deaminase, E-NTPDase: ectonucleoside triphosphate diphosphohydrolase, ALT/AST: alanine aminotransferase/aspartate aminotransferase ratio, IL-: interleukin, TNF-α: tumor necrosis factor-alpha.
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Obesity, overweight and sedentary behavior
The response of monocytes, lymphocytes, or peripheral blood mononuclear cells (PBMCs) in obese patients has been evaluated predominantly by aerobic exercise sessions, performed in different schemes and intensities, such as continuous and moderate- intensity [33], continuous and high volume (marathons) [34], high-intensity intermittent exercise (HIIE) [21] [35] [36] and higher efforts (to exhaustion) [37] [38] [39]. Slusher et al. [33] applied a 30-minute session of continuous aerobic exercise at 75% of peak oxygen consumption (V̇ O2peak) in obese and eutrophic individuals. The authors demonstrated that the exercise session reduced the synthesis of interleukins- 6 and 10 (IL-6 and IL-10) and pentraxin-related protein (PTX-3) in lipopolysaccharides (LPS)-stimulated PBMCs in both groups, but the synthesis of tumor necrosis factor- alpha (TNF-α) remained unchanged. From a clinical point of view, these findings may be considered negative for obese individuals, since they already present less synthesis of IL-10 in LPS-stimulated PBMCs at rest. However, due to the similar response to the eutrophic group after physical exercise, this suggests a balanced response of PBMCs to the inflammatory stimulus, endorsing the need for further studies with a continuous aerobic session of moderate intensity. Additionally, continuous aerobic exercise with high volumes, such as the marathon, led to reduced expression of toll-like receptor (TLR-4) gene in obese and lean individuals immediately after the race. Still, 24-h after the race an increase in gene expression was observed, as well as a decrease in the protein content [34]. Due to the strenuous nature of the marathon, the inflammatory potential was reflected by the systemic increase in IL-6, IL-10, and TNF-α, however, the concentrations of TNF-α and C-reactive protein remained high after 24-h. Furthermore, the monocytosis observed during acute exercise is frequently associated with increases in monocyte chemoattractant protein type-1 (MCP1) and other chemotactic factors, suggesting monocyte migration to inflamed tissue (i. e. muscle tissue) during the bout [34].
On the other hand, HIIE is used as an alternative strategy to achieve similar adaptations from traditional moderate aerobic exercise [40]. Compared to exhaustive physical exercise (stepping up and down from a step), 10 bouts of 60 s (at 85–90% maximal aerobic velocity (MAV)) differentially altered the subpopulations of CD4+T cells in obese individuals, increasing the proportion of cells expressing anti-inflammatory markers [35]. In addition, PBMCs incubated with the serum collected after the HIIE session showed less expression of transcription nuclear factor- kappa B (NF-κB) and histone H4 acetylation, reduced synthesis of IL-6 and TNF-α, and increased synthesis of IL-10 [35]. Unlike, PBMCs incubated with serum collected after an exhaustive session showed greater release of TNF-α, histone H4 acetylation expression, and membrane depolarization [35]. These results were accompanied by a higher anti-inflammatory systemic profile after the HIIE session compared to the exhaustive session [35].
In addition, similar responses were found in overweight-obese or sedentary individuals after the same HIIE protocol (10 bouts of 60 s (at 85–90% MAV)), with an increase in the histone deacetylase 2 activity in PBMCs, accompanied by an increase in IL-10, transforming growth factor-beta (TGF-β), and IL-6 blood concentrations [36] or an improvement in the proportion of memory Treg cells (mTreg) and a decrease in memory T effector cells (mTeff), as well as an increase in CD39 expression, and CD73 on the surface of CD4+T cells [24], respectively. CD39 and CD73 are ectonucleotidases responsible for the metabolism of adenosine triphosphate (ATP) into intracellular adenosine, contributing to the immunosuppressive function of Treg cells and reducing the production of inflammatory cytokines and chemokines [41] [42] [43]. Therefore, HIIE protocols appears to be a good strategy for reducing pro-inflammatory signaling in PBMCs, as well as regulating the T cell subpopulations. Furthermore, Gustafson and coworkers [44] identified a positive correlation Treg mobilization during endurance exercise and% body fat, suggesting greater benefits of exercise to induce immunoregulatory properties, as well as the participation of adipose tissue in lymphoid cell mobilization.
Research has been conducted on possible changes in oxidative stress and apoptosis after a maximum aerobic exercise session. After a maximum progressive aerobic test (maximum test) on the treadmill, the PBMCs of obese individuals showed higher protein expression of anti-apoptotic Bcl-2 and the LC3-II/LC3-I ratio, and lower protein expression of pro-apoptotic Bax compared with eutrophic individuals. Interestingly, the same study showed that after exercise the Bax/Bcl-2 ratio was negatively correlated with the body mass index (BMI) and waist and hip circumferences, and the LC3-II/LC3-I ratio was positively correlated with BMI, waist and hip circumferences, and fasting insulin blood concentrations [38]. These findings suggest that the PBMCs of obese individuals exhibit a greater increase in autophagic flow and less apoptosis after the maximum exercise compared to eutrophic individuals, possibly through a regulatory mechanism for survival in the inflammatory environment [38]. On the other hand, after maximum test on the treadmill, there was a reduction in DNA damage and increase in the content of intracellular total glutathione (GSH) in unstimulated PBMCs from trained and sedentary obese individuals and only lean sedentary individuals. However, after 1-h there was an increase of DNA damage and thiobarbituric acid reactive species (TBARS) production only in obese individuals [39]. Additionally, the PBMCs of sedentary obese individuals stimulated with hydrogen peroxide (H2O2) showed greater DNA damage and less total GSH compared with sedentary eutrophic subjects and trained obese subjects after the maximum exercise session [39]. The exhaustive exercise also increased the inflammatory monocytes percentage, histone H4 acetylation and reduced the histone deacetylase 2 activity in obese individuals [37]. The same study showed an increase in the inflammatory cytokines’ secretion in PBMC and an increase in systemic markers of oxidative damage after exhaustive exercise. Together, these findings show the requirement for caution in the maximum exercise prescription when aiming at anti-inflammatory and antioxidant effects in the obese population.
On the other hand, the effects of an acute session of strength exercise on immune cells in obese individuals are still not well characterized. In post-menopausal obese women, resistance exercise sessions (3 sets x 80% 1RM, 10 exercises) blunted the LPS-stimulated IL-1β and TNF-α production by whole blood cells [45], suggesting downregulation of TLR-4 in innate immune cells linked to inflammatory response. In lean volunteers, monocytosis was observed immediately after a single session of resistance training consisting in 4 sets of leg press, knee extensor and leg curl at 65% of 1-RM [46]. Interestingly, monocytes recruited after strength exercise sessions had a nonclassical phenotype, characterized by higher CD16+expression, proinflammatory functions and express higher levels chemokine receptors and integrin molecules on the cell surface which indicates their migratory capacity [47] [48]. However, resistance exercise had little impact on Treg and CD8+T cell mobilization compared to endurance exercise, suggesting that physiological differences between exercise types may alter the acute immune response [49]. The same group identified superior effects of endurance exercise to activate the axis of programed cell death protein 1 (PD-1)/aryl hydrocarbon receptor signaling in CD8+T cells, important signaling to cell survival a function, compared to resistance exercise in healthy males [50]. Given the importance of strength-based exercise in the treatment of obesity, future studies should be conducted to evaluate the acute effects of strength exercise or combined strength plus endurance exercise sessions on monocyte and T-cell mobilization in obese individuals.
The immune cell mobilization during acute exercise seems to be mediated by the adrenergic response and systemic cytokine levels in obese individuals. During exercise, natural killer (NK) cells, myeloid cells (neutrophils, monocytes, and dendritic cells), and T and B cells are recruited from lymphoid and non-lymphoid organs to the peripheral circulation for an effective immune response against non-self-particles (i. e., pathogens and allergens) or danger-associated molecular patterns (DAMPS). In a cancer murine model, exercise-induced infiltration of NK cells in the tumors was dependent on IL-6 signaling. In this sense, a recent study demonstrated that IL-6 receptor blockade attenuated the mobilization of NK cells (−53%) and DC cells (−66%) of obese men induced by an endurance exercise bout, through abolishment of IL-6 receptor signaling [51]. Since IL-6 is one of the most recognized myokines, we postulate that exercise-induced myokine release from contracting skeletal muscle may impact immune cell mobilization during acute exercise. Furthermore, adrenergic response directly impacts on leukocytosis [52]. In healthy lean individuals, the preferential mobilization of NK cells, non-classical monocytes and central and effector memory CD8+T-cells were largely dependent of catecholamine signaling through the β2-Adrenergic Receptor. However, there is a lack of evidence regarding catecholaminergic impact on immune cell mobilization of obese human individuals. In obese mice model, exercise modulates β2 adrenergic regulation of innate function of monocytes, mainly the phagocytic activity, and induced an anti-inflammatory profile [53] [54]. In this sense, both adrenergic response and IL-6 may crosstalk during physiological stress conditions [55], and the acute release of both mediators may contribute to the anti-inflammatory phenotype of circulating immune cells during exercise. In fact, the incubation of resting mononuclear cells of obese men with plasma obtained immediately after HIIE elicited higher frequencies of CD4+CD25+T cells expressing CTLA-4, CD39, and CD73, suggesting a role of blood factors released during exercise to induce an immunoregulatory phenotype of CD4+T cells [35]. Furthermore, high-fat diet-induced obese mice subjected to an acute bout of treadmill exercise presented increased signaling of IL-6 and immunoregulatory IL-10 concomitant to the proportion of F4/80+CD11c+M1 macrophages in adipose tissue, suggesting a role of exercise-induced myokine release on immunoregulatory properties of immune cells [56]. However, acute endurance exercise did not change the immune cell population, including macrophages and T cells, of adipose tissue from obese men, despite the reduction in adipose tissue progenitor cells [57].
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T2MD or insulin resistant
Glycemic control and inflammatory profile in T2DM are important variables modulated by the acute exercise session. Predominately light to moderate intensity in continuous aerobic exercise sessions [58] [59] and HIIE [14] has been investigated, however, no data regarding strength exercise were found in the literature search. Individuals with T2DM and healthy controls underwent an HIIE session characterized by 7 bouts of 1-min intervals at 85% of peak power output (PPO) with 1-min rest periods at 15% PPO [14]. Immediately after HIIE, there was an increase in the number of CD16+and classic monocytes and lymphocytes, as well as a reduction in the expression of TLR-2 over classic and CD16+monocytes in both groups after 1-h. Cellular changes were accompanied by reduced production of TNF-α stimulated with LPS in whole blood culture and blood circulating concentrations of TNF-α after 1-h. These findings suggest similar anti-inflammatory effects in individuals with or without T2DM after a HIIE session [14].
Of note, the increase in CD16+monocytes in individuals with T2DM after HIIE session was accompanied by a reduction in inflammatory response by decreasing in the TLR-2 expression [14]. However, a different anti-inflammatory response was found after 60 minutes of cycling at 60% of V̇ O2peak [59]. Additionally, in the same study the total number of monocytes and lymphocytes increased, however, accompanied by a reduction in the percentage of CD16+monocytes of individuals with obesity and insulin resistance. Interestingly, the percentage of CD16+monocytes was positively correlated with BMI, waist circumference, HOMA1-IR, insulin, triacylglycerol, very low-density lipoprotein (VLDL-c) and total cholesterol [59]. Therefore, mobilization and anti-inflammatory responses on CD16+monocytes appear to be dependent on the modality and intensity of aerobic exercise, most likely due to adrenergic mechanisms and endothelial shear stress [52] [60]. In addition, acute exercise increases insulin-induced activation of AKT Thirosine308-phosphorylation in adipose tissue resident macrophages of HFD mice concomitant with increased SOCS3 and STAT3 phosphorylation, suggesting that changes acute increases in insulin sensitive in macrophages of obese men is linked to an anti-inflammatory phenotype [56]. In line with this, obese insulin resistant men presented increases in insulin-binding circulating monocytes after prolonged aerobic exercise [61]. Acute ameliorations of immunometabolic response of monocytes to exercise may help to decrease the hyperresponsiveness of innate cells to the action of immunoregulatory IL-10 concomitant to low action of binding of insulin in these cells [62].
Regarding autophagic capacity, 60 minutes of aerobic exercise at 50% of V̇ O2peak was not enough to reverse the impaired autophagic flow of PBMCs of pre-diabetic subjects compared to healthy subjects [59]. The same study showed that treatment with rapamycin (pharmacological mTOR inhibitor) also did not reverse the imbalance in the autophagic flow in the prediabetic group, thus, despite mTOR being associated with inhibition of autophagy and possibly linked to the pro-inflammatory profile of PBMCs in patients with T2DM [63], it is possible that the very low intensity exercise session did not sufficiently stimulate the autophagic regulatory pathways.
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MetS
Studies evaluating the effects of the acute exercise session on the response of monocytes and lymphocytes of individuals with MetS are still scarce in the literature. Despite the use of unconventional exercise protocol, Wonner et al. [64] verified the influence of a 60-second session or even exhaustion (fixed power of 400 W on cycle ergometer) on leukocytes of individuals with MetS, risk of MetS and healthy control group. After the session, there was an increase in the lymphocyte count and monocyte subpopulations in all groups, as well as an increase in the percentage of intermediate and non-classic monocytes. However, the study did not verify the morphofunctional characteristics of these cells. Moreover, the lipid profile was modulated in individuals at risk for MetS, with no change in the MetS group, suggesting an insufficient stimulus for lipid modulation in this group. It is important to mention that, due to the greater capacity of intermediate and non-classic monocytes to patrol the endothelium and potential adhesion in the endothelial wall (marginal reservoir), acute exercise preferentially modulates these cells into the bloodstream mediated by β2-adrenergic receptors [52]. Interestingly, it is suggested that this mechanism contributes to the protective effect on endothelial health [64]. Furthermore, in a mice model of MetS exercise alleviates insulin resistance through downregulation of TLR4-mediated ERK/AMPK signaling pathway in tissue resident macrophages, demonstrating that exercise may acutely change metabolic parameters through the reduction of inflamed innate cells [65].
Taken together, the scarcity of studies on the effects of an acute exercise session on the proportion and morphofunctional characteristics of monocytes and lymphocytes of individuals with metabolic diseases makes comparative analysis difficult. In summary, except for exhaustive aerobic protocols, a moderate-intensity continuous aerobic exercise session or HIIE seem to be good strategies to counteract the inflammatory environment. Thus, the greatest possible number of acute exercise sessions developed throughout the week (respecting the recovery period) could be an effective strategy to maximize gains from the transient anti-inflammatory effect of each exercise session. Therefore, in the next topic, we will elucidate the influence of the practice of physical exercise in the long term.
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Chronic adaptations to the training period
Since systemic inflammation have a central role in metabolic diseases, such as MetS, obesity, NAFLD and T2DM, the modulation of monocytes, lymphocytes and PBMCs can be an important tool for anti-inflammatory effects. For example, the reduced release of TNF-α by PBMCs was associated with reduced glycemic responses and a lower circulating concentration of TNF-α after training period [66]. Additionally, the physical training is considered a good tool to reduce reactive oxygen species (ROS), fat content and inflammation in the liver, contributing to the treatment of diseases like NAFLD [67]. However, the type, intensity and volume of exercise are variables normally associated with the type of adaptation generated but with uncertain response regarding immune adaptations in metainflammation diseases.
Therefore, here we will discuss the influence of different chronic stimuli on monocytes, lymphocytes, and PBMCs of individuals with metabolic diseases, in order to describe possible similarities and differences in the adaptations provided ( [Tables 2] and [3] ). The variety of possibilities may favor adherence to training and, consequently, contribute to disease treatment.
Design |
Exercise protocol |
Results |
Other information |
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Barry et al. (2018) [69] 2 groups (30 to 65 y)
|
|
|
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Barry et al. (2017) [68] 2 groups (30 to 65 y)
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|
|
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Soltani et al. (2020) [90]2 groups (F, 18 to 25 y)
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|
|
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Habermann et al. (2015) [82] 4 groups (F, 50 to 75 y)
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Campbell et al. (2008) [91] 2 groups (M, 50 to 75 y)
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|
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Markofski et al. (2014) [13] 3 groups
|
|
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Da Silva et al. (2019) [86]2 groups (M)
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|
|
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Quiroga et al. (2020) [89]2 groups (7 to 12 y)
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|
|
|
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Streese et al. (2020) [72]2 groups (50 to 80 y)
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Ibrahim et al. (2018) [92] 4 groups (M, 19 to 26 y)
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After training (basal): There were no differences in% body fat and salivary antimicrobial proteins |
Bartlett et al. (2017) [70] ]2 groups (18 to 60 y)
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Colato et al. (2014) [71]1 group (M and F above 18 y)
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Colato et al. (2017) [79] 2 groups (F)
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Woods et al. (1999) [78] 2 groups (no gender distribution reported)
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Schaun et al. (2011) [88]2 groups (M, 54±4 y)
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LaPerriere et al. (1994) [73]2 groups (M, 18 to 40 y)
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Timmerman et al. (2008) [93]2 groups (65 to 80 y)
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Bartholomeu-Neto et al. (2015) [87]2 groups (F)
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Coen et al. (2010) [94]3 groups (40 to 65 y)
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Nickel et al. (2011) [34]3 groups (M, 30 to 60 y)
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Soltani et al. (2020) [75]2 groups (F, 10 to 25 y)
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Baturcam et al. (2014) [76] 2 groups (M and F, 35 to 45 y)
|
|
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Wadley et al. (2021) [77]2 groups (M, 30 to 46 y)
|
|
|
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van der Zalm et al. (2020) [81] 2 groups (M and F, 30 to 53 y)
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|
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Note: MICT: moderate-intensity continuous training, HIIT: high-intensity intermittent training, HRmax: heart rate maximum, VO2peak: peak oxygen consumption, RM: maximum repetition, CCR5: C-C chemokine receptor type 5, CCR2: C-C chemokine receptor type 2, CXCR2: C-X-C motif chemokine receptor 2, CXCL10: C-X-C motif chemokine ligand 10, HOMA2-IR: Homeostasis Model Assessment 2 for insulin resistance, IRF3: interferon regulatory factor 3, TG: triacylglycerol, TC: total cholesterol, HDL: high-density lipoprotein, LDL: low-density lipoprotein, NLRP3: NLR family pyrin domain containing 3, IRS-2: insulin receptor substrate 2, MMP-9: matrix metalloproteinase-9, TBARS: thiobarbituric acid reactive substance, AOPP: advanced oxidation protein products, T-SH: total thiol, MyD88: myeloid differentiation factor 88, CRP: C-reactive protein, JNK: c-Jun N-terminal kinase, sCD163: soluble cluster differentiation 163, IP-10: Interferon-inducible protein 10, GM-CSF: granulocyte-macrophage colony-stimulating factor, IL-: interleukin, TNF-α: tumor necrosis factor-alpha.
Design |
Exercise protocol |
Results |
Other information |
---|---|---|---|
T2DM or insulin resistant |
|||
Reyna et al. (2013) [97]
T2DM (n=11, 50 y) |
|
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Liu et al. (2015) [101] 3 groups (no gender distribution reported)
|
|
|
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Robinson et al. (2015) [96] 2 groups (30 to 65 y)
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Wenning et al. (2013) [98] 1 group (M, 47 to 77 y)
|
|
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Annibalini et al. (2017) [102] 2 groups (M, 50 to 70 y)
|
|
|
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De Matos et al. (2019) [22] 3 groups (18 to 55 y)
|
|
|
|
MetS |
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Steckling et al. (2019) [106] 1 group (F, 53.87 y)
|
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Martins et al. (2016) [103] 2 groups (55 to 65 y)
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|
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Note: MICT: moderate-intensity continuous training, HIIT: high-intensity intermittent training, HRmax: heart rate maximum, VO2peak: peak oxygen consumption, RM: maximum repetition, TLR: toll-like receptor, JNK: c-Jun N-terminal kinase, NF-κB: nuclear factor kappa B, NEFA: non-esterified fatty acids, HbA1c: glycated hemoglobina, hs-CRP: high-sensitivity C-reactive protein, sICAM-1: soluble intercellular adhesion molecule-1, TG: triacylglycerol, TC: total cholesterol, HDL: high-density lipoprotein, LDL: low-density lipoprotein, IGFBP-3: soluble insulin-like growth factor binding protein-3, IGF-1: insulin-like growth factor-1, HLA-DR: human leukocyte antigen, IL-: interleukin, TNF-α: tumor necrosis factor-alpha, INF-γ: interferon-gamma.
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Obesity, overweight and sedentary behavior
From an immunological point of view, an increasing number of studies have been analyzing the influence of HIIT and MICT protocols on immune cells in obese and sedentary individuals [68] [69] [70]. In a training model designed to decrease changes in body fat. Barry et al. [68] engaged obese and sedentary individuals in the following protocol, 2 weeks (5 days a week) of HIIT or MICT. Individuals from HIIT group performed 4×1 min to 10×1 min intervals at 90% HRreserve with 1 minute of active recovery and individuals from MICT group performed 20 min to 50 min continuous up to ̴65% HRmax. Despite similarities between the results, such as no differences in monocyte and lymphocyte counts and no reduction of classic monocytes expressing CXCR2, the HIIT protocol increased the percentage of classic monocytes, intermediate monocytes and T cells expressing CCR5, while MICT protocol decreased the percentage of intermediate monocytes positive for CCR2 and CXCR2 expression. The findings suggest that MICT protocol may reduce the monocyte migration (via reduced MCP-1 receptor) and HIIT protocol positively regulates monocyte and T cell migration (via increased MIP-1α receptor). Additionally, the same HIIT and MICT protocol was used by the same research group in order to verify the anti-inflammatory action of IL-10 and IL-6 in obese and sedentary individuals [69]. After the training period, there were no changes in the expression of the IL-6 and IL-10 receptor, count of classic monocytes and T cells and concentration of circulating cytokines (TNF-α, IL-6 and IL-10). However, in whole blood culture stimulated with LPS, both protocols reduced the anti-inflammatory action of IL-10 and IL-6, and HIIT group showed greater impact. Another study compared the effect of 10 weeks of HIIT (15 to 60 seconds of repeated sprints at 90% HRmax) or MICT (30 to 45 minutes at 70% HRmax) on the function of monocyte subpopulations in sedentary individuals [70]. Neither protocol changed the monocyte and lymphocyte count, but both increased phagocytosis of classic monocytes and the percentage of monocytes displaying oxidative burst, as well as reducing the percentage of intermediate monocytes and expression of TLR-2/4 in CD16+monocytes. However, interestingly, the HIIT but not the MICT reduced the percentage of non-classical monocytes. In addition, monocytes seem to be less activated after both moderate-intensity combined exercise training and short-term HIIT, as identified by lower HLA-DR expression on the monocyte cell surface, which suggests that exercise changes the inflammatory activation status of monocytes in obese individuals [22] [71]. Additionally, HIIT seems to favor epigenetic mechanisms that protect against oxidative stress [72], as well as the MICT increased the number of CD4+and CD8+T cells (with no change in the total number monocytes) after training period [73]. Taken together, HIIT and MICT protocols appear to promote immune modulations, such as reducing the population of CD16+monocytes and the expression of TLR-2 and 4 in these cells, restoring the balance between monocyte subtypes and contributing to negative regulation inflammatory profile in obese individuals. On the other hand, compared to the adaptations induced by MICT, HIIT protocol seems to potentiate the innate response of monocytes against stress challenges, evidenced by increase in migration receptors and greater production of TNF-α after anti-inflammatory stimulus. These findings may be linked to the nature of high-intensity exercise, providing greater contact with inflammatory agents, like LPS [74]. The same is seen in obese marathon runners, where 10 weeks of intermittent or continuous aerobic training (40 km per week) increased gene expression of TLR-4 and 7 in PBMCs, regardless of systemic benefits (reduction of ox-LDL) and body weight [34]. However, a recent study showed that vigorous HIIT downregulated TLR-4/MyD88/NF-κB axis and reduced TNF-α production by peripheral monocytes of obese men [75]. Exercise training also modulates the functional activities of immune cells of obese individuals. In this sense, Baturcam and coworkers [76] described lower expression of CCR5 and RANTES in subcutaneous adipose tissue, despite no changes in the phenotype of circulating monocytes and lymphocytes in obese individuals after exercise training, suggesting the impact of chronic exercise on leukocyte chemotaxis. Recent data shed light on physical activity effects on monocyte tethering and migration in obesity. A higher physical activity pattern in obese individuals was associated with reduced migration and tethering of CD16+inflammatory monocytes, despite little effect on chemokine receptor expression [77].
Other intensities of continuous aerobic training have also been demonstrated as possible strategy for immunological modulation. For example, no change in total monocyte and lymphocyte count and percentage of TCD4+and TCD8+cells was found after 6 months of light to moderate intensity aerobic training (40 minutes of treadmill at 50 to 60–65% V̇ O2peak) in sedentary subjects [78]. On the other hand, 12 weeks of moderate-intensity deep water running training increased the peripheral frequency of CD4+and CD8+T-cells in association with higher adiponectin and lower cortisol levels in overweight-obese women, suggesting changes in neuroendocrine axis by exercise training may impact the proportions of peripheral lymphocytes [79]. Similarly, 12 weeks of combined endurance plus strength training increased the frequencies of CD4+and CD8+T cells through changes in body fat composition [71]. The enhancement in T cells frequencies after exercise training may be linked with the modulatory effects of exercise training on BDCA-1+dendritic cells phenotype of obese individuals, which prime the cellular adaptive immunity response [80]. Interestingly, HIIT is linked to strong immunoregulatory actions and one-week of HIIT increased CD39+Treg phenotype in sedentary obese men [21]. Furthermore, increases in structured physical activity program increased Treg frequency without changes in body composition of obese individuals who engaged in lifestyle change program [81].
After 12 weeks of aerobic training (45 min at 60–70 to 70–85% HRmax), the DNA repair ability in PBMCs was not altered in overweight/obese sedentary individuals [82]. Similarly, 12 weeks of walking/running (30 to 60 minutes at 50 to 70% of HRreserve) did not promote changes on gene expression of IL-1β, TNF-α, IFN-γ, IL-10, insulin receptor substrate 2 (IRS-2) and matrix metalloproteinase-9 (MMP-9) in PBMCs of sedentary individuals. However, there was an increase in the systemic anti-inflammatory profile and a reduction in body fat after training [83]. Therefore, these findings suggest the need to use methods more accurately to assess the functionality of cells, for example secretion of cytokines associated with protein expression, in which could detect possible changes after the training period.
Resistance training is practiced worldwide and used as a strategy not only to induce skeletal muscle adaptations (hypertrophy and strength), but also is an important protective factor against chronic diseases [84] [85]. Markofski et al. [13] applied 12 weeks of strength training in overweight or obese sedentary individuals. The authors showed an increase in the population of intermediate monocytes only in overweight but not in obese individuals, with no changes in the percentage of monocytes expressing TLR-4. Additionally, after traditional strength training or with flow restriction (4 sets of 23 repetitions at 30% of 1-RM), sedentary overweight individuals showed beneficial effects on monocyte subtypes [86]. In this study, there was a reduction in the percentage of non-classical monocytes and expression of CD16 in CD14+monocytes, as well as an increase in the percentage of classical monocytes only in the group that performed the traditional training. The benefits of these changes were confirmed by reduction in the production of TNF-α with or without LPS stimulation [86]. On the other hand, the phagocytosis index and production of reactive oxygen species were not altered in PBMCs of sedentary individuals after traditional strength training [87]. Therefore, traditional strength training may be a good strategy for immunological modulation. However, some studies present limitations regarding different T lymphocyte subpopulations.
The combined exercise training (aerobic and strength) program also has been demonstrated be an alternative strategy to optimize the adaptations of both modalities. After 12 weeks of combined training, no differences were found on monocyte phagocytosis capacity [87] [88], expression of TLR-4, NF-kB and interferon regulatory factor 3 (IRF3) in PBMCs [89] [90] and no difference on T lymphocyte proliferation and CD3+, CD4+and CD8+number [91] [92]. On the other hand, a reduction in the expression of NLRP-3, caspase 1 and osteopontin was found in PBMCs of obese individuals after 12 weeks of combined training, 2 times/week [89]. Additionally, sedentary individuals after 12 weeks of combined training (3 times/week) demonstrated lower production of LPS-stimulated TNF-α in whole blood culture [93]. Interestingly, the same study showed that the overall reduction in the percentage of intermediate monocytes was positively correlated with the overall reduction in LPS-stimulated TNF-α in whole blood culture. Corroborating these results, 10 weeks of combined training reduced the percentage of intermediate monocytes in sedentary individuals treated with pharmacological compound rosuvastatin, compared with individuals who only received the pharmacological compound rosuvastatin [94]. These findings demonstrate anti-inflammatory benefits by reducing the proportion of CD16+monocytes after combined training. The differences found between the studies may be related to the characteristics of the exercise protocol performed and the high individual variability.
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T2MD or insulin resistant
Some past studies hypothesized that the exercise training mode directly impact on the inflammatory milieu of T2MD and insulin resistant individuals. In this regard, Balducci and coworkers (2010) [95] showed that high-intensity endurance training and high-intensity combined endurance plus strength training led to superior effects on the management of cytokines over 12 months in diabetic individuals. On the other hand, low-intensity endurance exercise training increased the systemic TNF-α levels concomitant to decreased IL-4 concentrations in diabetic patients. Thus, the type, intensity and mode of exercise may play a role on cell phenotype and, consequently, systemic inflammation of diabetes individuals. Robinson et al. [96] submitted pre-diabetic individuals to 2 weeks of HIIT (4×1 min to 10×1 min intervals (90% HRmax) interspersed with 1 min active recovery) and MICT (̴65% HRmax progressing from 20 min to 50 min). After both training protocols, there was a reduction in the expression of TLR-4 over monocytes and lymphocytes and a reduction in TLR-2 over lymphocytes. Despite the reduction in circulating glucose concentrations occurring only in the MICT group, both groups showed a positive metabolic effect by reducing the systemic concentration of fructosamine [96]. Additionally, 8 weeks of HIIT (12 cycling exercise bouts of 60 s, at 80 to 110% of the peak power) reduced the proportion of non-classical monocytes, increased the proportion of intermediate monocytes and decreased the expression of HLA-DR on intermediate monocytes of action insulin resistant individuals [22].
Nonetheless, individuals with T2DM submitted to 15 consecutive days of aerobic training (4 x 8 min at 70% V̇ O2peak followed by 2 min of rest) showed no changes in TLR2, TLR4, ERK and JNK phosphorylation, and p65 NF-kB protein content in PBMCs [97]. In the same study, although individuals increased insulin sensitivity, there were no changes in circulating concentrations of glucose, insulin, glycated hemoglobin (HbA1c) and non-esterified fatty acids (NEFA). Similarly, after 12 weeks of continuous aerobic training (15 to 45 min of cycling at a HR corresponding to a 2 mmol/L lactate threshold), there were no changes in CD4+and CD8+T cells, subpopulations of T cells (Treg, memory and naïve), HOMA-IR and circulating concentrations of glucose, insulin, HDL-c and triacylglycerol, except for the reduction in resistin, LDL-c, and total cholesterol [98]. Of note, Reyna et al. [97] prescribed the intensity and volume of each session similar to the MICT protocol by Robinson et al. [96], however, the protocol was two-minute passive intervals during the 15 sessions, which may explain, at least in part the divergent findings between studies. Additionally, the protocol proposed by Wenning et al. [98] was performed close to 2 mmol/L lactate threshold, possibly representing a low intensity stimulus [99] and contributing to the absence of alteration of the studied T cell subpopulations. On the other hand, pre-diabetic older subjects who engaged to 3 weeks of both concentric exercise training or eccentric exercise training presented increases in the proportions CD4+CCR7+CD45ro+central memory cells, CD8+CCR7+CD45ro- naïve cells, and CD8+CCR7+CD45ro+central memory cells after both trainings [100]. Given the role of premature immunosenescence in the progression of T2DM, the rejuvenating effects of eccentric or concentric exercise training on peripheral T-cells may have a prominent clinical significance. Taken together, the findings suggest anti-inflammatory benefits of both HIIT and MICT on monocytes and lymphocytes.
Resistance training is an interesting strategy to assist in the prevention and control of T2MD, stimulating the reduction of the concentration of HbA1c, increasing the GLUT-4 and increasing the insulin sensitivity [84]. To date, few studies have evaluated the influence of resistance training on monocytes and lymphocytes of individuals with T2DM, however, some studies have investigated the influence of combined training on PBMCs of individuals with T2DM [101] [102]. Individuals with T2DM who underwent 12 weeks of combined training (10–30 min of aerobic exercise at 40–60% V̇ O2peak and strength exercise, 2 sets of 8–10 repetitions at 50–60% 1RM) showed lower TLR-4 gene and protein expression compared to individuals with T2DM in pharmacological treatment (without exercise), as well as lower HOMA-IR and lower concentrations of insulin, glucose, HbA1c and IL-18 [101]. Additionally, after 16 weeks of combined training (30 to 60 minutes of walking at 40 to 65% of HRreserve plus 2–4 sets of 20 to 12 repetitions at 40 to 60% of 1RM), the PBMCs of individuals with T2DM and overweight individuals showed higher expression of insulin-like growth factor-1 (IGF-1) and reduced expression of IL-6 and IGF-binding protein 3 compared with the T2DM control group [102]. The same study demonstrated lower circulating concentrations of total cholesterol, TNF-α, IL-6, MCP-1, leptin and retinol binding protein 4 (RBP4) and increased IGF-1 in exercised T2DM group. Therefore, similar to the aerobic training alone, the combined training seems to be a good strategy to reduce the inflammatory and metabolic dysfunctions of T2DM.
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MetS
MetS patients underwent 30 weeks of combined training (30 to 45 min of moderate to relatively fast speed walk (measured by rating of perceived exertion) plus 3 sets of 10 repetitions at 70% 1RM) and purinergic activity of lymphocytes was evaluated [103]. After training, the lymphocytes of patients with Mets showed a reduction in the hydrolysis of ATP, ADP and an increase in the activity of the enzyme adenosine deaminase, reaching similarity with the control group. These findings suggest anti-inflammatory activity of lymphocytes, since the adenosine molecules (regulated by adenosine deaminase) promote suppression on the proliferation of T cells and the secretion of pro-inflammatory cytokines [104] [105]. On the other hand, after 12 weeks of HIIT (4×4-min at 90% HRmax with 3 min active recovery at 70% HRmax between intervals) there were no changes in the gene expression of TNF-α, p65 NF-kB, IL-6 and IL- 10 in PBMCs of women with MetS [106]. However, the training protocol decreased circulating concentrations of glucose, leptin, resistin, ghrelin, TNF-α, IL-6, IL-18 and INF-γ and increased of IL -10 and adiponectin, curiously, without reduction of body fat [106] . These findings suggest the need for detailed evaluations of the subpopulations of cells that compose PBMCs, as well as the possible participation of resident immune cells, macrophages for example, on secretion of cytokines in patients with MetS. In summary, it seems that combined training is a promising strategy to optimize the regulation of inflammatory response of lymphocytes.
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#
Monocytes and lymphocytes physical exercise-induced morpho-functional changes in metabolic diseases
Metabolic diseases originate from multifactorial processes, such as external factors (sedentary lifestyle, unhealthy eating and tobacco) [107] [108] and internal factors (genetics, polymorphisms, inefficiency of proteins and enzymes) [109] [110]. Integrating these multifactorial manifestations has not been an easy task, due to unclear mechanisms of mediation of signaling pathways. However, the influence of behavioral aspects such as sedentary behavior and poor dietary intake on the development of metabolic diseases is well discussed. Thus, mechanisms based on local inflammation of the gastrointestinal tract [111] [112] or adipose tissue [113] have been proposed as protagonists in the development of systemic inflammation associated with metabolic diseases ( [Fig. 1] ).
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It is recommended that individuals with obesity should exercise for at least 250 min/week at a moderate-to-vigorous intensity, spread over 3–5 days and achieve a total weekly energy expenditure>1500 kcal [114] [115]. Obese individuals should to prioritize whole-body aerobic exercises (e. g., walking, rowing, stepping) and be complemented by resistance exercises (2–3 days/week at 60–70% of 1RM) [114] [115]. In addition to being offering structured exercise interventions, individuals with obesity should also be stimulated to increase their daily life physical activity level (e. g., taking the stairs, walk or cycle more often to cover smaller distances, etc.) and to reduce the hours spent sitting [114] [115] [116]. Increasing habitual physical activity levels and participation in structured exercise training is considered as a class 1 A intervention in the treatment of obesity [114] [115] [116]. Interestingly, a limited number of studies which evaluates the daily life physical activity level of obese participants.
A recent study published by Verboven and Hansen [117], critically demonstrates that the assumption that physical exercise will lead to a substantial decrease in adipose tissue mass in obese individuals no longer contributes to current observations in clinical practice. In contrast, physical exercise should be a powerful tool to target cardiometabolic risk, physical fitness, and quality of life. In agreement with the statement of Verboven and Hansen, previous studies from our research group and colleagues have demonstrated that both intensity and duration of physical exercise seem to be determinant to establish an anti-inflammatory environment, improving cardiometabolic health, polarization of macrophages (M2), and expansion of Tregs and Th2 lymphocytes [8] [20] [24] [27] [28] [29] [30] [118] [119] [120] – which is more comprehensively elucidated in health, aging and metabolic diseases (see review Padilha et al. [120]; Cabral-Santos et al. [29] [118]). Here we propose highlighting the potential mechanisms involved in morpho-functional changes in monocytes, lymphocytes and PBMCs induced by different intensities and types of physical exercise in metabolic diseases.
HIIT is well-known to be time-efficient, a session is consisted by maximal effort and higher energy expenditure [121]. Previous studies have demonstrated the higher the intensity the greater is adrenergic discharge (catecholamines) [31] [40] and metabolic stress [32] [122]. The sympathetic nervous system controls diverse biological processes such as heart rate and blood flow, and major responsible for the ‘‘fight or flight’’ response that is provoked by acute stress. Most tissues, such as, lymph nodes, adipose tissue and skeletal muscle are innervated by sympathetic nervous system fibers and highly diverse cell types respond to sympathetic nervous system neurotransmitters through cell surface G protein-coupled α- or β-adrenergic receptors (ARs) [123]. Stress-induced activation of the sympathetic nervous system influences the activity of enzymes and proteins, as well as immune responses [124]. During acute high and moderate intensity exercise, there is an increase the glucose uptake by translocating the glucose transporter- 4 (GLUT-4) in skeletal muscle [125] and increase of IL-10 secretion stimulated of LPS [30]. Acute adrenoceptor stimulated by physical exercise activates the cholinergic anti-inflammatory pathway [126]; the autonomic nervous system interacts with the immune system modulating the inflammatory process [127]. Neural-immune interaction is known as cholinergic anti-inflammatory pathway, an endogenous, physiological mechanism by which acetylcholine from the valgus nerve, via the α7 sub-unit of the nicotinic acetylcholine receptor (α 7nAChR), interacts with the innate immune system to modulate and restrain the inflammatory cascade [127] [128]. Specifically, acetylcholine, the main vagal neurotransmitter, attenuates the release of pro-inflammatory cytokines TNF-α, IL-1β, IL-6 and IL-8, but not the anti-inflammatory cytokine IL-10 [127].
In immune cells, β2 adrenergic signaling stimulates the preferential mobilization of inflammatory phenotypes, such as CD16+monocytes and CD8+T-cells into the bloodstream after physical exercise session [103]. These cells, especially senescent T cells, are mobilized to the peripheral tissues and undergo apoptotic stimuli, stimulating the creation of an “vacant space” where new cells will be matured and replaced in the circulation [104]. Thus, the vacant space theory contributes to the reduction in inflammatory lymphocytes in inflammation associated with metabolic diseases. The practice of physical exercise stimulates redistribution in the proportion of these cells in the long-term.
In addition to the increase in catecholamines during physical exercise, the contraction of skeletal muscle stimulates a low and transient increase in myokines, such as IL-6, during each exercise session [105]. This scenario results in upregulation of anti-inflammatory cytokines (IL-10 and IL-1ra), leading to the increase in regulatory immune cells that manage the inflammation resolution [105] [106]. The anti-inflammatory and catabolic environment provided by the physical exercise sessions modulates signaling pathways of energetic sensors, such as AMPK and mTOR in monocytes and lymphocytes, leading to metabolic reprogramming with predominance of oxidative phosphorylation [94]. In fact, the increase in the oxidative pathway for ATP resynthesis is necessary for the anti-inflammatory characteristics of monocytes and lymphocytes [94] [107], therefore, this mechanism is promising for the inflammatory control in metabolic diseases.
Together, the increase in catecholamine concentration, the transient increase in anti-inflammatory cytokines, and the regulation of energy substrates during physical exercise sessions can be crucial for the increase in regulatory monocytes and lymphocytes and control of inflammation associated with metabolic diseases ([Fig. 2]). It is worth mentioning that all types of physical exercise presented in this review were good anti-inflammatory strategies, however, low intensities may not provide sufficient stimulus. Additionally, exhaustive exercise, especially aerobic, should be prescribed with caution when aiming at an anti-inflammatory environment.
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Future perspectives and conclusion
This perspective review highlighted the intensity and type of physical exercise as a potential determinant of changes in monocyte and lymphocyte phenotypes in individuals with metabolic diseases. In relation to the aerobic exercise acute session, except for exhaustive practice, HIIE and moderate intensity continuous exercise are good anti-inflammatory strategies. Although strength exercise is an important tool for musculoskeletal, metabolic, and cardiovascular adaptations, future studies should evaluate the contribution of a single session, isolated or combined with aerobic exercise, on the modulation of monocytes and lymphocytes of individuals with metabolic diseases. In the long term, HIIT, MICT, strength, and combined training protocols are effective in providing anti-inflammatory adaptations. It is worth mentioning that, even though many patients with metabolic diseases have difficulty in performing certain physical exercises, the progression of intensity to at least moderate levels should be encouraged, in order to provide better immunological adaptations.
Finally, from an immunological point of view, we strengthen the wide variety of training protocols available to negatively regulate the inflammatory environment in individuals with metabolic diseases. The variety of possibilities could favor adherence to training and, consequently, contribute to treatment ( [Fig. 3] ).
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Conflict of Interest
The authors declare that they have no conflict of interest.
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Correspondence
Publication History
Received: 01 December 2021
Accepted: 09 December 2021
Accepted Manuscript online:
13 December 2021
Article published online:
18 February 2022
© 2022. Thieme. All rights reserved.
Georg Thieme Verlag
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Germany
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