Acknowledgments
The MIUR (PRIN2012) contributed to the fellowships to NM.
Cells have evolved multiple and sophisticated stress response mechanisms aiming to prevent macromolecular (including proteins, lipids, and nucleic acids) damage and to maintain or re-establish cellular homeostasis. Heat shock proteins (HSPs) are among the most highly conserved, ubiquitous, and abundant proteins in all organisms. Originally discovered more than 50 years ago through heat shock stress, they display multiple, remarkable roles inside and outside cells under a variety of stresses, including also oxidative stress and radiation, recognizing unfolded or misfolded proteins and facilitating their restructuring. Exercise consists in a combination of physiological stresses, such as metabolic disturbances, changes in circulating levels of hormones, increased temperature, induction of mild to severe inflammatory state, increased production of reactive oxygen and nitrogen species (ROS and RNS). As a consequence, exercise is one of the main stimuli associated with a robust increase in different HSPs in several tissues, which appears to be also fundamental in facilitating the cellular remodeling processes related to the training regime. Among all factors involved in the exercise-related modulation of HSPs level, the ROS production in the contracting muscle or in other tissues represents one of the most attracting, but still under discussion, mechanism. Following exhaustive or damaging muscle exercise, major oxidative damage to proteins and lipids is likely involved in HSP expression, together with mechanically induced damage to muscle proteins and the inflammatory response occurring several days into the recovery period. Instead, the transient and reversible oxidation of proteins by physiological concentrations of ROS seems to be involved in the activation of stress response following non-damaging muscle exercise. This review aims to provide a critical update on the role of HSPs response in exercise-induced adaptation or damage in humans, focusing on experimental results where the link between redox homeostasis and HSPs expression by exercise has been addressed. Further, with the support of in vivo and in vitro studies, we discuss the putative molecular mechanisms underlying the ROS-mediated modulation of HSP expression and/or activity during exercise.
Cellular stress response represents an adaptive protective mechanism to maintain or re-establish cellular homeostasis so to survive under unfavorable environmental conditions, such as heat shock, hypoxia and oxidative damage [1]. The mechanisms of stress response commonly include a transient down-regulation of growth related proteins, whereas the production of specific stress-response proteins increases. Strictly dependent on type, intensity and duration, the stressing stimulus can promote either cell survival with adaptation to adverse conditions or the elimination of excessively damaged cells [2].
Heat shock proteins (HSPs) are the most highly conserved stress response proteins during evolutionary history [1]. In humans, they display different functions depending on tissue specific localization, intra- or extracellular distribution, developmental expression, level of induction and the client proteins they interact with (Table 1). As common mechanism of action, HSPs recognize unfolded or misfolded proteins and facilitate their restructuring in either an ATP-dependent (large HSPs) or energy independent manner (low weight HSPs) [3]. Indeed, HSPs not only protect the cells against proteotoxic stresses but they have also a critical role in normal functioning of several cellular processes, such as the assembly of multiprotein complexes and the transport of proteins across cellular membranes [4] and [5]. Moreover, HSPs are fundamental for the maintenance of cell structural integrity, interacting with cytoskeletal elements, influencing their formation and function, and protecting them during proteotoxic stress [6]. Under several stress conditions, HSPs are highly up regulated by heat shock factors (HSFs) in order to maintain cellular homeostasis and to enhance cell survival functions [7].
Heat shock protein | Localization |
---|---|
Hsp110 (HSPH2) | Cytosol/nucleus |
Hsp90 (HSPC1) | Cytosol |
Hsp70/Hsp72*(HSPA1A) | Cytosol/nucleus |
Hsc70 (HSPA8) | Cytosl/nucleus |
Hsp60 (HSPD1) | Mitochondria |
αA crystallin (HSPB4) | Cytosol/nucleus |
αB crystallin (HSPB5) | Cytosol/nucleus |
Hsp25/Hsp27 (HSPB1) | Cytosol/nucleus |
Hsp22 (HSPB8) | Mitochondria |
Hsp20 (HSPB6) | Cytosol/nucleus |
always referred as Hsp70 throughout the text
The most characterized HSPs families include the Hsp90 (HSPC) family, with five well-characterized members, the Hsp70 (HspA) group with 13 members, the Hsp60 (HSPD) family with only one form, mostly found in the mitochondrial matrix, and the family of the small HSPs (sHSPs), which includes 11 members, among which are the well-studied members Hsp27 (HSPB1) and αB crystallin (HSPB5) [8].
Voluntary muscle contraction is associated with a production of several stressors generated for example by metabolic disturbances, changes in circulating levels of hormones, increased temperature, induction of mild to severe inflammatory state, increased production of reactive oxygen and nitrogen species (ROS and RNS), and other free radicals [9] and [10]. Skeletal muscle and other tissues distinguish the different signals which are specific to the nature, intensity and duration of exercise, so that the categorization of exercise stressors and exercise-induced stress response can vary greatly depending upon which type of exercise protocol has been utilized [11]. During acute exercise, the type and the magnitude of stress response depend on the short-term modification of cellular homeostasis and on the repair of damage eventually inflicted to cellular components [12]. Conversely, in exercise training programs, with repetitive exercise administered in a “chronic” form, the stress response plays a role in the accumulative physiological adaptation that maintains homeostatic balance, and it represents a crucial component of the cellular and molecular mechanisms by which regular exercise confers protection against related and unrelated stressors [13]. Since exercise consists in a combination of physiological stresses, it is not surprising that it acts as a potent HSPs inducer. Their increase following voluntary muscle contraction in muscle and other tissues is strictly related to the type and magnitude of exercise stressors [14]. For instance, while non-muscle damaging isotonic contractions involve mostly the modulation of Hsp70 and Hsp60, eccentric contractions, considered as a muscle damaging exercise, involve also the phosphorylation and translocation of small HSPs [15].
Among all factors involved in the exercise-related modulation of HSPs level, the ROS production in the contracting muscle or in other tissues represents one of the most attracting, but still under discussion, mechanism [16]. The majority of reports have assumed that, during exercise, the skeletal muscle provides the main source of ROS and RNS. These molecules play an important role, not only in the skeletal muscle adaptation to exercise, but also in the muscle plasticity that occurs during a period of prolonged inactivity. Low/moderate amounts of ROS produced during regular muscle contraction are considered to evoke specific adaptations, such as an increased activity of antioxidant and/or oxidative damage repair enzymes, increased resistance to oxidative stress and lower levels of oxidative damage [17]. ROS function as messenger in exercise-induced adaptive gene expression and exercise can be considered a potent hormetic conditioner [18].
The variations in exercise type and protocol utilized in different studies, the differences in subject characteristics within and between studies [10], as well as the difficulty of the direct measurement of ROS production in living systems [19], pose clear limitations to our understanding of the net contribution of exercise-induced ROS in the modulation of HSP response. Nevertheless, the transient and reversible oxidation of proteins by physiological concentrations of ROS seems to be involved in the activation of stress response following non-damaging endurance-type of exercise, while mechanical disruption of protein structure and secondary inflammatory processes are likely involved in the stress response following forms of “damaging” exercise [10].
In the following sections of this review, we provide a critical update on the role of HSPs response in exercise-induced adaptation or damage in humans, then focusing on experimental results where the link between redox homeostasis and HSPs expression by exercise has been addressed. Further, with the support of in vivo and in vitro studies, we discuss on the putative molecular mechanisms underlying the ROS-mediated modulation of HSP expression and/or activity during exercise.
It is widely accepted that acute or chronic exercise modulates the activity and the expression of HSPs in several human tissues such as the skeletal muscle, as well as in circulating monocytes and lymphocytes, or body fluids [20], [21] and [22]. Moreover, results from animal studies clearly indicate that any forms of exercise induce changes in the level of HSPs in spleen, heart, liver, kidney, placenta, brain and spinal cord [23], [24], [25], [26] and [27]. As already indicated, the magnitude of the exercise stress plays a major role in the stress response [14], while with a repetitive exercise, the initial response of some HSPs can be lower as training progresses [10]. The exercise induced changes in HSPs seem to have multiple cytoprotective effects on mitochondria and on sarcoplasmic reticulum and cytoskeleton components [28], [29] and [30], inhibitory effects on apoptosis [31], as well as a role in the maintenance of enzymatic activity, insulin sensitivity and glucose transport [32] and [33].
Most of the human studies from endurance aerobic and resistance anaerobic exercises refer to the modulation of Hsp70 in skeletal muscle and/or in circulating monocytes [20], [34], [35], [36] and [37]. Hsp70 is the most abundant of all HSPs [38], accounting for 1–2% of cellular protein being highly represented in skeletal muscle. It is known that a single bout of exercise is sufficient to increase Hsp70 in skeletal muscle at both mRNA and protein levels in an intensity dependent manner [14]. Differently from other HSPs, baseline levels of Hsp70 are increased by prolonged exercise training [39] and [40], while mechanical unloading determines a decrease in the Hsp70 content in muscle [41]. Recently, Cobley et al. [42] demonstrated that aging was associated with a lower Hsp70 increase post acute exercise in the vastus lateralis of untrained and trained old subjects, although the increase in Hsp70 was greater in trained compared with untrained individuals.
As molecular chaperones, Hsp70 helps the correct refolding of nascent proteins and interacts with unfolded proteins to avoid inappropriate interactions and degradation of damaged proteins [43]. In addition, it has a role in protein translocation, anti-inflammatory responses, control of cell signaling, modulation of immune response and chronic disease conditions, such as diabetes, obesity, and insulin resistance [44]. Indeed, a growing number of evidences from animal studies verify the relevance of exercise-induced Hsp70 in the maintenance of cellular functions and disease prevention. Smuder et al. [45] show that the increase in Hsp70 by endurance exercise was related to protection against myofiber atrophy and contractile dysfunction induced by mechanical ventilation in rat diaphragmatic muscle. In regard to disuse muscle atrophy, there are indeed several lines of evidence that induction of Hsp70 content can protect against the negative biochemical and structural changes associated with muscle atrophy [41]. Similarly, in a localized model of spinal cord injury, exercised rats had significantly higher levels of neuronal and astroglial Hsp70, a lower functional deficit, fewer spinal cord contusions and fewer apoptotic cells than non-exercised rats [27]. It has also been shown that Hsp70 has cardioprotective features in rat and mouse models of ischemia-reperfusion injuries but, although exercise is very effective in promoting the accumulation of Hsp70 in the heart, it seems that this increase per se is not essential for exercise-induced cardioprotection [46].
Even though the exercise stress response can be differently dependent on temperature in various tissues [9], studies have also shown that increase in temperature alone is not sufficient to determine the typical exercise-induced expression of HSPs [47]. Several papers demonstrated that the increase in Hsp70 gene expression in human muscles during or immediately after exhaustive exercises correlates with the degree of glycogen depletion [35], [48] and [49], while Ogawa et al. [50] suggested that ATP level in plasma is a trigger of Hsp70 release after exercise. On the contrary, a study from Morton et al. [51]demonstrated that carbohydrate availability does not affect the increase in Hsp70, Hsp60 and αB-crystallin content induced by high-intensity intermittent training in human vastus lateralis and gastrocnemius. Beside these conflicting results on the potential role of carbohydrate availability as a contributing factor to the exercise induced expression of HSPs, direct evidences about the mechanisms underpinning these findings are still missing.
The damage of the cytoskeletal myofibrillar structure and small lesions in the membranes of muscle cells, with or without simultaneous signs of inflammation and necrosis, can be caused by exercise depending on type of contraction, intensity and volume [52] and [53]. Elevated serum or plasma levels of myoglobin and CK activity can reveal protein leakage from skeletal muscle, while loss of desmin mostly relates to the sarcomeric disruption and Z-disk streaming [54].
Several articles documented that muscle-damaging exercise induces up-regulation and phosphorylation of Hsp27, αB-crystallin and Hsp70 proteins, with or without translocation from a diffuse cytosolic location to insoluble fraction, corresponding to the Z disks [53] and [55]. Thompsons et al. [56] and [57] demonstrated that single or repeated bouts of eccentric exercise increase the mRNA and protein content of Hsp27 and Hsp70 in elbow flexor or biceps muscles of untrained volunteers. In addition, the lower baseline levels of both proteins, measured in the previously exercised muscle before the repeated bout, suggest an adaptation consequent to the first bout of exercise. Similar results have been reported by Vissing et al. [58], where the up-regulation of Hsp27 and Hsp70 was induced only after eccentric, damaging exercise, with an attenuated response at both mRNA and protein levels after the repeated bout. It is well known that small HSPs play an indispensable role in the maintenance of cell integrity through their interaction with intermediate filaments, neuro-filament and actin fibers [59] and [60]. The interaction of sHSPs with actin seems to be tightly dependent on their phosphorylation: non-phosphorylated Hsp27 was found to bind actin fibers’ends and it prevents their polymerization, whereas the activated phosphorylated form can prevent actin fibers ‘aggregation. Similarly, the phosphorylation of αB-crystallin at both Ser45 and Ser59 residues inhibits actin fiber depolymerization induced by cytochalasin D, thus preventing their stress-dependent aggregation [61]. Therefore, small HSPs play a pivotal role in protecting the cytoskeleton against contraction-induced injury in muscle cells [62] and [63]. Indeed, the group of Truls Raastad in Oslo demonstrated that maximal eccentric exercise induces a rapid accumulation of Hsp27 and αB-crystallin in the myofibrillar fraction of vastus lateralis at 30’ post-exercise, while the increase in Hsp70 protein in the cytosol and its translocation to the cytoskeleton components was evident only 24 h and 4 days post-exercise respectively [15]. In 2009, the same group investigated the subcellular localization of the HSPs in the myofibrillar structure from elbow flexors after maximal eccentric contraction. They showed that both Hsp27 and αB-crystallin accumulate in Z-disks and in areas of myofibrillar disruption, at the intermediate structures (desmin), to stabilize and protect the myofibrillar structures during and after unaccustomed eccentric exercise [63]. Recently, Frankenberg et al. [64] reported that total Hsp27 and αB-crystallin amounts did not change in vastus lateralis following any type of concentric or eccentric exercise, but the latter induced a rapid phosphorylation of these sHSPs and their partial redistribution from the cytosolic compartment to the myofibrillar fraction, although the sHSPs’ translocation was not dependent on their phosphorylation status. On the contrary, the Hsp70 protein content in the cytosolic compartment increased 24 h after the eccentric exercise, but without translocation to the cytoskeleton fraction [65].
Lastly, muscle damage, reticulocytosis and leukocytosis accompanied by lymphopenia are well-recognized phenomena related to severe molecular damage and apoptosis in blood and muscle cells following exhaustive exercise [66], [67] and [68].
The role of HSPs extends also outside the cells. Under stress conditions they can be released into the extracellular environment or enter the systemic circulation [69]. Extracellular HSPs, such as eHsp70, have been proposed as molecular mediators during injury since they act as immunological regulators signaling tissue damage to inflammatory cells and enhancing the innate immune response to resolve inflammatory events [70] and [71]. However, despite the clear correlation between exercise and cytokines production [72], data reported in the literature do not confirm cytokines as major players in the activation of exercise-induced stress response, especially when referring to non-damaging aerobic exercise. Following muscle damaging exercise protocols, the invasion of monocytes may be responsible for the exercise induction of HSP expression, either through cytokine production or through ROS generation [73].
Since the early 2000s, a series of scientific reports have described the putative relation between the specific induction of HSPs and ROS generated following acute exercise in humans (Table 2).
HSPs | Tissue | Type of exercise | References |
---|---|---|---|
Hsp70 | Skeletal muscle (VL) | Single-leg cycle ergometer | [74,75] |
Two-legged dynamic knee extensor | [76] | ||
Treadmill running | [22] | ||
Leukocytes | Half marathon | [79] | |
Marathon race | [82] | ||
Treadmill running | [80,81,85] | ||
Cycle ergometer | [86] | ||
Hsp90 | Leukocytes | Cycle ergometer | [91] |
Hsp60 | Skeletal muscle (V) | Single-leg cycle ergometer | [74,75] |
Treadmill running | [22] | ||
Hsp27 | Leukocytes | Half marathon | [79] |
Cycle ergometer | [91,86] | ||
αB crystallin | Leukocytes | Cycle ergometer | [91] |
VL, Vastus lateralis
Most of these studies have focused their attention on two major components of HSP's family, Hsp70 and Hsp60, whose redox-dependent induction by acute exercise is widely recognized [74], [75] and [76]. The direct evidence comes specifically from studies envisaging an antioxidant supplementation strategy. Indeed, it has been reported that supplementation with antioxidants such as vitamin C [75], γ-tocopherol/ascorbic acid cocktail [76] and N-acetylcysteine [77], although able “per se” to increase the basal level of HSPs, was effective in abolishing the Hsp60 and Hsp70 increase observed at the end of exercise in VL muscle. To get an indirect prove of the putative correlation between the exercise-dependent ROS generation and the alteration of HSPs expression, several authors have tried to measure the activity and/or expression of antioxidants enzymes as well as other markers of oxidative stress or redox imbalance, but the results obtained are not always convincing or consistent. For example, Khassaf et al. observed an increase of Hsp60 and Hsp70 in muscle after a bout of non-traumatic exercise with concomitant and transient rise in SOD activity [74]. On the contrary, any change in SOD or CAT activity was observed after exercise in their subsequent work [75]. Similarly, the peak of Hsp70, Hsc70 and Hsp60 induction in VL muscles from recreationally active subjects at 48 h after an acute bout of moderate running exercise protocol, did not correlate either to MnSOD protein content modifications, or to SOD and CAT activity modulation [22]. Although further investigations are needed, it could be assumed that the induction of HSPs observed in these studies may be due to a transient oxidative stress, which was not detectable by the methodological approach used. It is also known that specific antioxidant systems (i.e. GSH) are more sensitive to exogenous and endogenous oxidants than others (i.e. TRX system, SOD, CAT) [78]. Therefore, it is possible that the oxidative stress markers selected in those studies were not altered by ROS generated during this specific exercise activity.
The exercise-dependent induction of Hsp70 has been also described in blood cells (Table 2). Differently from skeletal muscle, it appears that in leukocytes this effect is related to a substantial oxidative stimulus that can be generated during strenuous endurance exercise [79], [80], [81] and [82]. In this specific context the oxidative stress-mediated increase of Hsp70 seems to take part in a wider protective mechanism including antioxidant enzymes or anti-apoptotic proteins such as MnSOD and Bcl-2 [82]. The ability of ROS in driving Hsp70 expression in blood cells after endurance exercise has been widely documented in studies conducted by Fehrenbach and colleagues [79], [80] and [83]. In particular, they observed that an exhaustive treadmill protocol or a half-marathon stimulates Hsp70 expression at pre-translational and protein levels in most of leukocytes populations of human subjects, up to 24 h after exercise. This effect is related to the activation of immunocompetent cells, particularly mono- and granulocytes that, under physical stress, are capable to produce relevant quantities of ROS [83]. A systemic neutrophil activation and degranulation due to the half-marathon were also mirrored in a rise of MPO and IL-8 in plasma [79], [80], [81], [82], [83] and [84]. These findings, together with the enhanced levels of Thyobarbituric acid reactive substances TBARs (TBARs), measured in lymphocytes from old men after maximal exercise test [81], suggest that the increase in Hsp70 could be due to an oxidative damage mainly localized in the cellular membrane.
As already described for skeletal muscle, the intervention with the antioxidant supplementations (i.e. RRR-α-tocopherol), has a suppressive role on the exercise-associated upregulation of Hsp70 transcription also in granulocytes. Particularly, this effect is active at 3 h post exercise but not at 48, suggesting a role for ROS in driving the early induction of Hsp70 protein synthesis in response to intensive exercise [80].
Thus, the cellular oxidative status seems to be involved in the modulation of Hsp70 expression levels: decreasing ROS production or increasing antioxidant capacity may limit the increase in Hsp70, as well as low levels of antioxidants or high levels of oxidative damage are associated with high Hsp70 expression. This has been documented in selected elderly people characterized by different levels of physical activity. In this group, the highly physically active subjects showed no changes in Hsp70 after acute exercise because of their higher antioxidant capacity, whereas the medium/low physically active subjects showed a higher percentage of lymphocytes, monocytes and granulocytes expressing Hsp70 with a concomitant increase in advanced oxidation protein products (AOPP) levels [85]. Nevertheless, it should consider that, beside the individual antioxidant capacity, the magnitude of HSPs response seems to be highly dependent from the specific basal level. As demonstrated by Ceci et al., the increase of Hsp70 and Hsp27 determined by a single bout of exhaustive exercise in elderly subjects resulted significant only in trained subjects showing the lower HSP basal expression related to a better redox homeostasis [86].
The sHSPs modulation following different types of exercise in humans has been widely described [35], [42], [87], [88] and [89], but evidences about the involvement of exercise-induced ROS in sHSPs expression are still lacking. Studies conducted by Morton and colleagues did not detect any increase in muscle content of Hsp27 and αB-crystallin after acute exercise in both young active subjects and aerobically trained athletes [47]. This may be due in part to the non-damaging nature of exercise protocol, which does not appear to cause any over structural or functional damage as well as any modification in oxidative stress-related markers (i.e. MnSOD, SOD and CAT). Indeed, whereas the Hsp70 and Hsp60 expressions seem to be linked to the general antioxidant response induced by ROS, the sHSPs appear more responsive to contractile-induced mechanical stresses and/or oxidative damage. Moreover, the baseline levels of these sHSPs are usually relatively high in human skeletal muscle and possibly sufficient to counteract any minor oxidative modification encountered during exercise. The only evidence about the relationship between acute exercise-induced ROS and sHSPs modulation has been provided by the work of Fehrenbach et al. [79]. This study revealed that the amount of Hsp27 was increased, at both mRNA and protein levels, in leukocytes of trained human subjects after half marathon. Since the increase in MPO and IL-8 reflects oxidative stress due to intensive endurance exercise [79] and [90], it is likely that exercise-induced generation of ROS may be partly responsible for the observed Hsp27 induction. Thus, it appears that the modulation of sHSPs is specifically dependent upon strong production of oxidative stress that occurs only at the end of a single bout, medium-high intensity, damaging exercise [86]. Indeed, when our group attempted to correlate the modulation of Hsp27 and αB-crystallin levels observed in leukocytes after maximal non-damaging exercise in healthy active adults to the induction of oxidative damage, no differences were detected in the amount of 4-HNE adducts in the total protein extract [91].
During the last decade, several studies have suggested that ROS induction by chronic exercise could promote an adaptation process able to modulate the expression of different HSPs in humans (Table 3). In fact, depending on the training status as well as type and intensity of the training protocol, it has been observed a close correlation between oxidative enzymes and stress-protein expression in specific tissues (i.e. skeletal muscle) [40], [90] and [92] and/or at the systemic level within bloodstream (i.e. leukocytes, serum) [93], [94] and [95].
HSPs | Tissue | Type of exercise | References |
---|---|---|---|
Hsp70 | Skeletal muscle (VL) | Electrically braked precision ergometer | [90] |
Leukocytes | Aerobic training | [95] | |
Explosive-type resistance training | [94] | ||
Hsp60 | Skeletal muscle (VL) | Treadmill running | [40] |
Hsp27 | Skeletal muscle (VL) | Running | [92] |
Serum | Aerobic training | [93] | |
Leukocytes | Explosive-type resistance training | [94] | |
αB crystallin | Skeletal mscle (VL) | Treadmill running | [40] |
Running | [92] |
VL, Vastus lateralis
To date, all published data seem in agreement to the concept that exercise training eliciting an increase in antioxidants are also able to elevate the levels of specific HSPs [40], [90], [92], [93], [94] and [95]. In particular, in skeletal muscle tissue, firstly Morton et al. [40] found that trained people have a significant increase in MnSOD, which correlates with a higher protein content of Hsp60, and αB-crystallin. Afterwards, Vogt et al. [90]have demonstrated that high-intensity training can raise the expression of several enzymes such as COX-1, COX-4, NADH6, and SDH with the concomitant increase of Hsp70 transcript level.
Similar correlation between antioxidants and HSPs’ response has been also found by Cumming and colleagues [92]. In this case, high-intensity endurance training reduces GPx1 protein levels and promotes a pro-reducing environment in skeletal muscle leading to the down-regulation of Hsp27 and αB-crystallin.
Given the role of skeletal muscle during performance, these results suggest the presence of an adaptation process to preserve redox balance through mitochondrial biogenesis and the overall remodeling of the cell, or that exercise promotes a pro-reducing environment, leading to the down-regulation of antioxidant enzymes and specific small HSPs.
Although different exercise protocols were utilized in those works, it remains surprising the selective modulation of only a specific small heat shock protein rather than other, or their simultaneously down-regulation [40], [90] and [92]. Differently, the lack of induction of Hsp70 is not surprising since, in all protocols, the sampling was carried out over the 24 h after the last training session and it is known that this protein is increased at the beginning of training, to facilitate adaptation to a stress of a novel homeostatic disruption; once the muscle recovers from the acute stress, Hsp70 returns to baseline levels [40].
Similarly to the results from skeletal muscle, our group found that at the end of a 12 weeks of non-damaging explosive-type resistance training in elderly subjects, the reduced level of Hsp70 and Hsp27 proteins in leukocytes were associated with a pro-reducing environment, as demonstrated by the decrease of thioredoxin reductase 1 (TrxR1) level and serum Myeloperoxidase (MPO) [94]. Moreover, Simar et al. [95] found that the decrease of chronic oxidative stress through the antioxidant supplementation was effective in reducing the Hsp70 expression in leukocytes.
In conclusion, all these data suggest that the modulation of redox homeostasis determined by repeated exercise-stressor during the training period may translate into physiological adaptations affecting the expression of antioxidants and specific stress-protein response as the aforementioned HSPs.
Besides the old view that ROS are just ‘harmful by-products’ of the aerobic metabolism, exercise-induced increases in ROS are now recognized as important mediators in signal transduction events involved in the activation of different transcription factors [96], [97], [98] and [99]. Thus, ROS production in the contracting muscle or in other tissues represents one of the more attracting exercise-related factors involved in the modulation of HSPs level.
It is well known that oxidative stress can induce a heat shock response. Indeed, ROS show a high reactivity toward sulfur-containing amino acids and metal-containing cofactor sites in proteins, causing reversible and irreversible inactivation of many different proteins and representing a major threat toward the cellular proteome [100]. Following exhaustive or damaging exercise, major oxidative damage to proteins and lipids is likely involved in HSP expression, together with mechanically induced damage to muscle proteins and the inflammatory response occurring several days into the recovery period. In this situation, the heat shock factors (HSFs)-mediated transcriptional control of HSP genes is traditionally suggested as the main molecular regulatory mechanism.
HSF represents a family of transcription factors induced by both stressful and non-stressful stimuli [101]. Four isoforms of HSF have been identified, three of which, HSF1, 2, and 4, are present in humans. HSF1 is ubiquitously expressed in mammalian tissues, HSF2 is expressed at very low levels in postnatal tissue while HSF4 is mainly expressed in the brain and lungs [102]. Under basal conditions, HSF1 exists in both the cytoplasm and nucleus in a latent monomeric state bound to multimeric complexes including Hsp70 or Hsp90. Under stress, HSF1 is displaced from the Hsp70 and Hsp90 chaperones, converted to a trimer which is required for the binding to the responsive heat shock element (HSE) of HSF1 in the Hsp promoters (Fig. 1). The promoters of HSP genes can contain more than one HSE, which allow a cooperative binding of multiple HSFs [3] and [102]. Phosphorylation of HSF1 provided by tissue and stress specific pathways is also required for activation [103].
HSF1 also shows an intrinsic stress-sensing capacity via two cysteine residues within the HSF1׳s DNA-binding domain that are engaged in redox-sensitive disulfide bonds [104]. Indeed, changes in cellular redox-state have been reported as a common feature of stress-induced activation of HSF1 in mammalian cells in response to both thermal and oxidative stress [105]. Thus, HSF1 activation might also be involved in non-muscle damaging exercise, where minor oxidative damage to proteins and a direct HSF1 modification by free radicals might occur [106]. It has been indeed demonstrated that the inhibition of ROS production by membrane-bound NADPH oxidase in dominant negative Rac1 HepG2 cells inhibits the stress-induced activation of HSF1 and the heat shock response [107].
Although the data collected so far, from both animal models and human subjects, are convincing with respect to the fundamental contribution of ROS in heat shock response, the mechanism of ROS induced HSPs’ modulation during exercise is far from being clarified, mainly because of the limited number of studies and conflicting results. HSF1 up-regulation, activation, translocation, and binding have been reported in cardiac hypertrophy induced by chronic exercise or after single acute bout of exercise in cardiac and skeletal muscle [108], [109] and [110]. However, Paroo et al. [111] reported that protein denaturation other than cellular redox status is likely involved in the physiological induction of HSF1-HSE DNA-binding activity in rat myocardium after an acute bout of intense treadmill exercise. Further, it has been demonstrated that exercise under elevated body temperature promoted cardiac protein oxidation, Hsp70 mRNA expression and Hsp70 protein accumulation without increase in myocardial nuclear localization of phosphorylated HSF1 [112], suggesting that other transcriptional or post-transcriptional regulatory mechanisms are involved in exercise-induced Hsp70 expression (Fig. 1).
Recent papers from in vitro studies published by our and other groups point out the presence of a variety of specific regulatory elements in the HSPs gene promoters, allowing the binding of different redox-sensitive transcription factors. Antioxidant response elements (AREs) have been identified in the promoters of Hsp70 and αB-crystallin, indicating a putative role for Nrf2 in the redox regulation of these two HSPs in HEK293 and murine skeletal myoblasts, respectively [113] and [114]. Even more, an AP-1-like site overlapping the most distal ARE motifs upstream of αB-crystallin gene allows the binding of c-Jun to that promoter region, cooperating with Nrf2 in the redox-dependent regulation of this sHsp in muscle cells [114]. Under normal conditions, Nrf2 is retained in the cytoplasm by the redox sensitive actin-binding protein Keap1, which targets Nrf2 for ubiquitination and degradation by the proteasome. An increase in ROS abrogates the Keap1-mediated degradation of Nrf2, which in turn accumulates in the nucleus where it binds to AREs to stimulate the expression of a wide arrays of antioxidant enzymes.
In 2014, Sasi et al. [115] identified the interaction of HSF-1, NF-Y (nuclear transcription factor Y), NF-κB (nuclear factor kappa B) and cAMP (cyclic adenosine monophosphate) response element binding protein (CREB) transcription factors with the promoter domains of murine Hsp70, which regulate constitutive as well as inducible Hsp70 expression in a coordinated manner under different stress conditions. Furthermore, it has been described that NF-κB drives the expression of the inducible form of Hsp90 in cancer cells by directly binding to a consensus sequence in the hsp90α gene promoter [116].
We need to take into account that the redox-dependent activation of transcriptional machinery can be effected through several different mechanisms, ranging from the direct oxidation or reduction of a transcription factor, to the involvement of redox-sensitive pathways far upstream in a signaling cascade from the transcription factor itself (Fig. 1).
Redox-sensitive kinases activated during muscle contraction include PI3K/Akt and AMPK, the MAP kinases p38 MAPK, JNK, and ERK (also called p44/42 MAPK) [117], [118], [119] and [120]. Most of them are implicated in the regulation of mitochondrial biogenesis [121] and [122], but also involved in the activation of HSF-1 [123], Nrf2 [124] and [125] NF-κB [126] and c-Jun [127]. In addition, some evidences suggest that redox imbalance may both directly activate HSF1 and indirectly other transcription factors through the intervention of thioredoxin system [114] and [128] (Fig. 1). Thus, depending on the type and duration of exercise stimuli, different redox-sensitive transcription factors (e.g., Nrf2, c-Jun and NF-κB) and transcriptional cofactors could have a relevant role in the HSP genes’expression.
As widely reported, the multifaceted functions of HSPs help to maintain the health of complex organisms. HSPs have been found to play fundamental roles in different stress conditions and to offer protection from subsequent insults. Being also released outside the cells, the function of HSPs during stress goes beyond their intracellular localization and chaperone role, and they have been proposed as a form of communication during injury, acting as immunological regulators and potentiating the innate immune response to resolve inflammatory events.
The physiological stresses associated with exercise have also been shown to modulate HSP content and activity in a broad variety of human and animal tissues. The HSP response to exercise might well account for many health benefits associated with increased physical activity, therefore, exercise intervention may provide protection against protein-misfolding diseases or during aging, controlling of systemic inflammation and preserving muscle function.
Among other stressors, it is likely that exercise-induced ROS could play a major role in the HSP expression, at least in non-muscle damaging exercise and during adaptation to training. Despite many studies speculate on the possible contribution of ROS and/or oxidative stress in the exercise-induction of HSPs in humans, a limited number of them specifically address this issue through the use of reliable biomarkers or antioxidant supplementation. Indeed, as detailed elsewhere in this volume, radicals are highly reactive and have a very short half-life, so the main limitation in understanding the net contribution of ROS in the activation of cell response by exercise depends upon the difficulty to measure directly their production in living systems. As a consequence, most of the reports addressing the HSP response elicited by increased ROS activity during exercise emphasize their potential damaging effects. Indeed, the biomarkers most utilized in the redox biology of exercise incorporate the measurement of antioxidants, the evaluation of oxidatively modified molecules or their ultimate cellular products (e.g., protein carbonyls, isoprostanes, malondialdehyde (MDA), 4-hydroxyl- 2-nonenol, 8-hydroxy-2-deoxyguanosine) and/or the measurement of cellular redox balance (e.g., GSH to GSSH ratio). Future researches on this topic would need to focus on the ability to obtain quantitative measures of the ROS production and to assess the redox status of cells and organelles from muscle and other tissues.
Because of the above, and also taking into account the additional methodological limitations for in vivo studies about the redox-signaling pathways and the molecular factors responsible for redox-regulating processes, data on the ROS-mediated modulation of heat shock genes’ expression derive mostly from cellular studies. Although it is well recognized that, independently from oxidative misfolding of proteins, cellular signaling pathways like p38 MAPK/ JNK/ERK and P13K/AKT can activate HSP expression by redox-sensitive transcription factors others than HSFs, the relevance of these mechanisms in the exercise-induced adaptation to exercise in humans is only speculative. Moreover, an important event frequently occurring in HSP response during exercise is the apparent discrepancy between the expression of RNA messages and those of their relative proteins. As highlighted in the previous sections, the increase in HSP protein levels in human skeletal muscle or in leukocytes can be detected either within 1–3 h or some days after the exercise, suggesting the occurrence of post-transcriptional or translational control on HSP expression. At present, no data are available on the putative involvement of exercise induced ROS in the post-transcriptional or translational control of HSP gene expression.
In conclusion, additional fundamental work is needed to elucidate the precise biological significance of ROS in the exercise-induced modulation of heat shock proteins and to unveil the role of this phenomenon in the adaptation to exercise training, also because of the relevance of exercise-induced modulation of HSPs in biological and pathological conditions linked to impaired redox homeostasis (e.g. aging, muscle atrophy, cardiovascular diseases).
Disclosure statement: The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.
The MIUR (PRIN2012) contributed to the fellowships to NM.
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