Rate of deterioration and recovery of performance and discomfort (DOMS) after an athletic activity

Deterioration of performance and difficulty in recovery is an aspect in sports that weighs heavily in athletes’ ability to engage in beneficial physiological adaptation to stress, marking the adaptative process their upper limit of achivement. Since in order for them to achieve high performance they must engage in fequent  bouts of strenous training, the discomfort DOMS (Delayed Onset Muscle Soreness) that irremediably follows subsequent to the  activity is  largely dependent on the magnitude of EIMD (Excercise-induced Muscle Damage) induced inflammatory response. Performance largely depends on how the adaptive process that follows EIMD is managed. DOMS  its manifestation, must be dealt with individually according to each particular subject’s sensibility to excercise, in order that enhancement of performance is favored and maladaptation is avoided.

A pattern of the adaptive process has been called Training Adaptation Syndrome and its evolution in time after a training challenge or event can be clearly appreciated form the graph. New challenges should not be undertaken unless until the recovery has lead to the re- establishment of the full ability to function. This of course is a time lapse that varies with the individual but which may in some cases exceed 48hrs.

 

Also how improvement of performance with training of the athlete and adequate recovery/adaptation is progressively achieved, can also be appreciated in the graphs shown above and below, leading to the morphological re-organisation of the functional systems that physical exercise puts under stress. Only then higher performance may be mastered.


 

However despite the extensive literature and investigation on the subject, the process is not well understood. This lack of clear understanding has motivated resorting to empirical methods for managenment of DOMS which consist mostly in applications of cold and cryotherapy, static compression, intermitent peristaltic compression, massage, nutrution, heat-related treatments, trekking poles, ultrasound and electrical current modalities,  hyperoxia or hypoxia, laser therapy, spa therapy, mechanomyographical feedback, vibration therapy, acupuncture, and homeopathy. Almost all are costly and time consuming and among them only massage has shown statiscally significant improvement in reducing soreness, but shows only limited results in transfer to performance enhancement.

In this essay DOMS will be examined and depicted according to the best scientific research that could be found, hoping to give a clearer rendering of what it consists of and seeking a better understanding by athletes, opening perhaps better ways for performance enhacement without the risk of overeaching and falling into maladaptive outcomes. How DOMS affects the adaptation process will be then especially considered.

What is DOMS?

This question cannot be definitely answered, but lately recent discoveries have given a better idea of what it is in essence. To begin with it remarkably ressembles a response to sepsis.

 

Response of muscle to exercise resembles closely to the innate immunity release of alarmins, pro-inflammatory cytokines (e.g., IL-1β, TNFα) and of pro-inflammatory M1 macrophages, in response to sepsis; as shown in the graph above 1Antagonist cytokines at the beginning of resolution (blue) phase will subsequently follow and also the release of soluble cytokine antagonists (e.g., IL-1Ra). Tissue repair at the final phase (green) involves the release of immunomodulatory type 2 cytokines (e.g., IL-10 and TGFβ) and stimulation of tissue resident regulatory T cells (Treg) and M2 macrophages. Potential roles of cytokines (IL-25 and IL-33, IL-6, IL-22), can promote activation of mesenchimal fibro-adipogenic precursor (FAP) cells and immune lymphoid cells (ILCs) to promote tissue repair.

Innate Lymphoid Cells

GroupCellsCell markersCharacteristics
ILC1NKCLin-aCD56lo.Recognize infected cells by the absence of MHC I molecules
ILC2Lin- CD117+/-CD127+ CD25+ ST2+, CRTH2+Roles in allergic asthma and muscle repair
ILC3LTi cellsLin- CD56- CD117- CD127- NKp44+ NKp46+Promote formation of secondary lymphoid tissues, role in mucosal immunity
ILC22Lin- CD56+ NKp44+ NKp46+ CD117+, CD127+Secrete IL-17A and IL-22 cytokines
Lineage negative (Lin-) cells are selected according to the methods of Ng, Fairchild [91] for the absence of specific cell surface markers.
Table n°1

More specifically in EIMD macrophages and FAPs contribute to effective debris disposal and together with Treg cells they sustain satellite cell proliferation/differentiation and contribute to the resolution of inflammation. However, in some cases the original damaging noxa cannot be removed and maladaptive muscle remodeling takes place with persistent inflammation with recruitment of autoreactive T cells (CD4+/CD8+) ending in substitution of myofibers with noncontractile elements such as fat and fibrotic tissue2.

A significant correlation between CRP and a calculated score based on IL-1β and IL-6 levels has been reported during EIMD3. The response to the two cytokines is cooperative or synergistic and the correlation was calculated using normalized values of all patients from all points in time and an appropriate model for the synergistic action of IL-6 and IL-1β as suggested by Ganter et al. 4. Although EIMD is not generally regarded as an Acute Phase Reaction, the correlated elevation of CRP suggests that it is bordeline showing evidence of systemic innate immunity response. EIMD and its manifestation DOMS can be considered as typical aseptic inflammation.

The adaptive response

As shown above, repeated episodic bouts of muscle contraction, associated with frequent exercise training, are potent stimuli for physiological adaptation. Skeletal muscle demonstrates remarkable malleability in functional adaptation and remodeling in response to contractile activity over time 5,6. Training-induced adaptations are reflected by changes in contractile protein and function  7,8, mitochondrial function 9, metabolic regulation 10, intracellular signaling 11, and transcriptional responses 12. The molecular mechanisms that govern the adaptation to training involve a gross gradual alteration in protein content and of enzyme activities. These progressive changes reflect activation and/or repression of specific signaling pathways that regulate transcription and translation, and exercise-responsive gene expression. Transient postexercise changes in gene transcription, early involve genes, myogenic regulators, genes of carbohydrate (CHO) metabolism, lipid mobilization, transport and oxidation, mitochondrial metabolism and oxidative phosphorylation, and transcriptional regulators of gene expression and mitochondrial biogenesis 12,13,14,15. A single bout of exercise alters the DNA binding activity of a variety of transcription factors, including MEF2 16,17, and NRFs 18,19. Protein stability and subcellular localization of transcriptional factor complexes within the nucleus and mitochondrion are also affected 20,21,22. Moreover, Egan et al. (2013) have recently shown that transient DNA hypomethylation of gene-specific promoter regions precedes increases in mRNA expression in response to acute exercise 23. These pulses of elevated mRNA during recovery in turn facilitate the synthesis of respective proteins to elicit gradual structural remodeling and long-term functional adjustments 24, which contribute towards maximizing substrate delivery, mitochondrial respiratory capacity, and concratile function during exercise. The net effect is optimal performance during future exercise challenges, with readaptation of homeostasis, or hormesis, characterized by biphasic dose responses of generally similar quantitative features with respect to amplitude and range of the stimulatory response that are either directly induced or the result of compensatory biological processes following an initial disruption in homeostasis25. Adaptation implies altered but optimal metabolic resource allocation  and eventually the establishment of an organismal state of enhanced resistance to peripheral fatigue 26,27, due to dimished sustained currents (signals) able to activate metabo-receptors sensory nerve endings outside of small arterioles and venules of fascia surrounding muscles bundles 28,29 and readily accessible to muscle produced fatigue-mediating metabolites 30.

31

The Molecular Basis of Adaptation to Exercise
Schematic representation of changes in mRNA expression (bottom panel) and protein content (middle panel) over time as a consequence of acute exercise and chronic (repetitive) exercise training. Although each individual bout of exercise is necessary as a stimulus for adaptation, it alone is insufficient to alter the muscle training-induced phenotype. Adaptation is therefore the consequence of repetitive stimuli deriving from the sum of individual exercise bouts.  An individual exercise bout elicits during recovery a rapid and transient increase in relative mRNA expression of a given gene. Several fold alterations in mRNA expression from basal levels are typical and peak at 3–12 hr after cessation of exercise, generally returning to basal levels within 24 hr. This pattern is specific to a given gene and to the exercise challenge. Translational processing together with elevation of postexercise mRNA  result in a modest, parallel boost in contractile protein content. Accumulation of repeated exercise bouts elicits the gradual increase of protein as response to the pulsed increases in mRNA expression. Thus, long-term adaptation to training is due to cumulative effects of many acute exercise bouts, leading to a new functional status. Training-induced changes in protein content or enzyme function resulting in improved exercise performance (upper panel), will impose further substarte and metabolic demands. Usually protein half-lives are much longer than those of mRNA,  making  changes in protein content more readily noticeable than changes in transcript expression and respectively so more in training as opposed to individual bouts of exercise.

The metabolic surge of myeloid cells during the innate immunity response to intense exercise must be added to the demands of muscle contraction and compensated for, in order for such optimal resouces allocation to be attained. Immunometabolic reprogramming will allow myelod cells to meet their functional demands under the conditions existing in the surrounding microenvironment, however the organism will account for this demand and sense it as a component of healthy acute fatigue. For the initial proinflammatory conditions of neutrophil recruitment, phagocytosis and NET formation) observed during intense exercise and afterwards during recovery (monocyte recruitment), glycolysis provides a rapid means for the generation of ATP and biosynthetic intermediates. Energy required for these and other functions are provided from a high rate of glycolysis 32. With relatively few mitochondria, neutrophils can receive electrons from glycolysis via the glycerol-3-phosphate (G6P) shuttle into complex III in order to maintain Δψ but hardly coupled to ADP phosphorylation by action of Complex V (F1/F0-ATPase). Although less efficiently, ATP is yielded faster by glycolysis to meet the demand; a precipitous ATP production while catabolic efficiency is sacrificed. But G6P can also enter the pentose phospahte pathway (PPP), a spinoff of glycolysis that generates reducing equivalents of NADPH necessary for the microbicidal mechanisms regulated by NOX and riboses essential for nucleotide synthesis, playing also  a significant role in the cellular redox status 33. This ensures that neutrophils can function in an inflammatory environment where the oxygen tension may be low or even absent 3435. Though the glycolytic process can also proceed aerobically 33.

Favorable recovery from exercise should be characterized by a prompt diminishing sense of fatigue and should not consist in more than –metabolite mediated– metabolic signaling,  to prevent further dangerous energy consumption (muscle damage, rhabdomyolysis, pathological myocardium remodeling and cardiac arrythmia 36, chronic fatigue, adrenal insufficiency 37) beyond diminishing returns 38. As noted, increased resistance to peripheral fatigue should be perceived with progressive training.

45

cfDNA

Findings of presence of cell free DNA in plasma during recovery from acute exercise have shed more light on the unanswered aspects of the section above: What is DOMS?. The source of cfDNA remains speculative, however, a rapid cfDNA accumulation due to active mechanisms seems likely rather than passive cell death events as previously suggested, however eventually ending in special forms of cell death.

Neutrophils can also kill pathogens extracellularly by releasing neutrophil extracellular traps (NETs; Brinkmann et al., 2004)39. A evolutionarily highly conserved first line defense mechanism of cellular transformation in which the nuclear membrane breaks down, DNA mixes with cytoplasm and the whole assemblage is jettisoned from the cell providing a key ingredient for pus and other exudates. They represent a physical structure to ensnare and immobilize bacteria and other micro-organisms in a mesh or net-like structure. Like a fly in a spider’s web, the organisms are stuck and can be further attacked by the antibacterial proteins that stud the DNA 39,40,41. Interestingly, histones have anti-bacterial activity, providing another example of a nuclear molecule doing double duty for the cell, fulfilling important functions in both the intracellular and extracellular space 42.The importance of NETs in microbial defense is underscored by their presence in pus. Superficial infections produce pus. For centuries, as Pisetsky (2011)43 pointed out in a recent review, pus with a high viscosity was regarded as “good” be- cause it resolved the infection. Now we know that pus consists mostly of neutrophils surrounded by NETs.

Molecularly, the few events that have been shown to be required, sequentially, are the production of ROS, the migration of the protease neutrophil elastase (NE) and later myeloperoxidase (MPO) from granules to the nucleus, the processing of histones, and eventually the rupture of the cell. Eventually, NETs are removed during the resolution of inflammation. The impact of NETs derives from the combined antimicrobial activities of granular components, histones, and some cytoplasmic proteins. Eosinophils and mast cells, which are granulocytes closely related to neutrophils, granulocyte homologues in lower vertebrates, and even plants release extra- cellular traps. NETs are the results of a unique form of cell death that morphologically is characterized by the loss of intracellular membranes before the integrity of the plasma membrane is compromised. To release NETs, activated neutrophils undergo dramatic morphological changes. Minutes after activation, they flatten and firmly attach to the substratum. After 1 h, the nuclear envelope disaggregates into vesicles and the nucleoplasm and cytoplasm form a homogenous mass. Finally, the cells round up and seem to contract until the cell membrane ruptures and the interior of the cell is ejected into the extracellular space, forming NETs (Video). Notably, despite the intermixing of cellular compartments, during the last phase of NETosis, <30 proteins are present in NETs. Most of them originate from granules, few are from the nucleus, and cytoplasmic NET components are rare.

44

Time-lapse recording of neutrophils undergoing NETosis. Neutrophils were stimulated with PMA, and a z stack was generated for 2 h and 25 min on a confocal microscope. Directly labeled antibody fragments against NE (green) and chromatin (red) in the supernatant depict formation of NETs in the final phase. 

cfDNA release

 

In addition to their function in the defense against infection, NETs may contribute to the pathogenesis of rheumatic disease. NETs are present at sites of tissue injury in vasculitis, promote thrombosis (an important concomitant of many connective tissue diseases) and represent an important source of DNA to form immune complexes and drive type I interferon production 45,46,47,48,49. Coagulation is a way to reduce blood loss after injury, but it also represents a primitive innate immune response that limits microbial spreading 50. Coagulation is an example of how the amount of NET formation can determine a “good” or “bad” outcome. NETs participate in timely clot formation, but if present in excess they induce massive coagulation that can stop the blood supply of organs, causing severe ischemia.

 

 

Excercise-induced inflammation and sports performance

EIMD and its associated inflammatory response is of paramount importance for athletes’ performance for two basic reasons: 1) the rate of deterioration and recovery of performance and discomfort (DOMS) after an athletic activity is largely dependent on the magnitude of EIMD-induced inflammatory response and 2) it affects the frequency of training stimuli, that is, the time needed for optimal recovery in between practices, official events, and/or an event and a practice. A >20% decline of the force-generating capacity of muscles exhibits a close association with the magnitude of muscle damage and its associated inflammatory response 51, 52, 53. Smaller reduction of muscle strength is usually not accompanied by histological evidence of EIMD 54. Paulsen et al  suggested that strenuous isolated eccentric activity produces a greater degree of EIMD than the so-called eccentrically biased activities such as downhill running or intense-level running. Evidence indicates that the magnitude of force, the degree of lengthening, velocity of movement, and overall volume of eccentric load are probably the most important factors dictating the rate of muscle injury in response to exercise 55, 56. In fact, it has been shown that EIMD induced by a football match is associated with the number of explosive types of movement that incorporate a strong eccentric component 57,58.

In cases of mild performance decline, defined by Paulsen et al.  as a drop of strength by <20%, creatine kinase activity (CK) in blood remains <1,000 U/L, inflammation is limited, and recovery is usually fast (within 12–48 h) independent of type of exercise 59,60,61,62,63,64. In the case of moderate performance decline, defined by Paulsen et al.  as a drop of strength by <20%–50%, myofiber necrosis may be observed (mostly in high-respondents)  , CK exceeds 1,000 U/L, the inflammatory response is more intense with leukocyte infiltration into the injured muscle, and degradation of structural and contractile proteins may be evident and recovery is usually completed within a week. 65,59,66,67,68.In the case of severe performance decline, defined by Paulsen et al8 as a drop of strength by >50%, necrosis is usually observed in parts of the myofibers, CK may exceed 10,000 U/L, soreness is quite high, muscle swelling is evident, the inflammatory response is intense and characterized by a marked accumulation of immune cells into the traumatized tissue, and recovery usually takes 1–3 weeks or even longer if strength loss is >70% 69,70,59,71,72,68,73,74,75,76,77,78. In severe EIMD, increased proteolysis and muscle disruption is observed, even during early recovery, due to disturbances in calcium homeostasis 53,79 In these three scenarios, athletes may need to use different recovery strategies in order to be able to train or compete as soon as possible. Recovery treatments may be classified in four major categories: 1) pharmacological (e.g., inflammatory agents, NF-κB inhibitors, estrogen therapy, phosphodiesterase inhibitors, ACE inhibitors), 2) nutritional approaches and supplements (e.g., antiantioxidants, herbal remedies, alcohol ingestion, ω-3-fatty acids, β-hydroxy-β-methylbutyrate, protease supplementation, nucleotide supplementation, tea consumption, beetroot, caffeine, creatine, enzyme supplementation, and carbohydrate and/or protein supplementation), 3) rehabilitation and physical therapy methods (e.g., cryotherapy, heat-related treatments, compressive loading techniques, trekking poles, ultrasound and electrical current modalities, massage, hyperoxia or hypoxia, laser therapy, spa therapy, mechanomyographical feedback, vibration therapy, acupuncture, and homeopathy), and 4) exercise-related treatments (e.g., stretching and low-intensity exercise), and numerous studies and reviews have examined their effectiveness in reducing EIMD and accelerating recovery 80,81,82,83. Of those, nonsteroidal anti-inflammatory agents (depending on dosage and time of ingestion), protein supplementation, β-hydroxy-β-methylbutyrate supplementation, massage (depending on the time of administration and technique used), antioxidant supplementation, and exercise-based treatments have been shown to exert positive action 30,31,32,33.  These recovery approaches aim to reduce swelling, improve blood flow, pain sensation, immune cell recruitment, and/or improve healing by activating satellite cells and anabolic factors as well as improving tendon healing. One has to remember that athletes are interested not only in the attenuation of the EIMD-related inflammatory response but also and more importantly in effective and timely performance recovery. Today, no general guidelines exist regarding the treatment of EIMD and performance recovery. Certain concerns have been raised regarding the use of anti-inflammatory agents based on reports suggesting that these products not only disrupt the inflammatory response but also hinder the adaptive response to training 848586However, the periods during which anti-inflammatory agents are used need to be discerned. There are training periods during which athletes need to compete and train with very high frequency (e.g., in-season training), and cessation would be beneficial. In contrast, there are periods during which athletes train aiming for long-term adaptations, and anti-inflammatory agents may disrupt both EIMD and training adaptations. In the latter case, athletes should rethink about using such recovery approaches. However, more research is needed in order to determine whether anti-inflammatory agents interfere with training adaptations.

Now it is also well-understood that athletes may be low-, moderate-, and high-respondents to EIMD, a fact that also explains the substantial interindividual variability in the responses seen following various types of exercise protocols used to induce muscle micro-injury 87,71,71,88,89,80,90,91,92. This phenomenon may be attributed to a number of factors such as age,93,94,95, preconditioning,96,97,95gender,98,99 genetics,100,101, physical conditioning level,57,102,103,104, and joint range of motion 105. Therefore, sport practitioners should determine whether their athletes are low-, moderate-, or high-respondents, be advised to establish individual normative values for each one, and avoid absolute comparisons among athletes or generalizations. It must also be mentioned that preconditioning, a phenomenon also known as “repeated bout effect,” may protect athletes from EIMD, that is, after a first session of damaging exercise, skeletal muscle tissue adapts and is less vulnerable to injury in subsequent sessions of the same type of exercise.93,97,106 In fact, it has been shown that repetition of a damaging exercise results in less EIMD, inflammation, oxidative stress, leukocyte infiltration, and strength loss. 107,108,68,106,109.

Excercise Performance

Dietary nitrate has the potential to reduce blood pressure, lower the oxygen cost of exercise, and, at least in some circumstances, enhance exercise capacity.

With regard to the effect of nitrate on indices of exercise performance in healthy volunteers, the literature appears consistent in showing that 2–6 days (or up to 15 days) of supplementation can increase indices of performance during high-intensity constant work-rate exercise and maximal incremental exercise 110111112. The effects of acute supplementation on performance are less consistent, with some studies showing a positive effect 113114115116  and others showing no effect  117118. It is likely that the efficacy of acute nitrate supplementation will depend on several factors such as the age, health, diet, and fitness/training status (including muscle fiber type proportions, capillarization, and baseline plasma [nitrite]) of the subjects tested; the intensity, duration, and nature of the exercise task; and whether the exercise is performed in normoxia or hypoxia. Acute nitrate intake may rapidly influence vascular tone and peripheral tissue oxygenation  113119, but more time may be necessary to permit changes in mitochondrial and contractile proteins to influence exercise performance  120121. Whether longer-term nitrate supplementation may support or augment (or even hinder) the physiological adaptations to training is presently unknown.

The duration of continuous maximal exercise for which nitrate appears to be ergogenic is in the range of 5–30 min 110122. There is limited evidence that nitrate is beneficial for longer duration exercise (>40 min) performance, at least when administered acutely  117123. This may be related to the lower intensity of such exercise and the associated reduced likelihood of the development of local mismatching of perfusion to metabolic rate in muscle (i.e. loci that are relatively hypoxic and acidic). Whether nitrate supplementation may be ergogenic during very high-intensity continuous or intermittent exercise has not been systematically evaluated. However, two studies indicate that high-intensity intermittent exercise performance might be enhanced by nitrate supplementation 122116.

Mechanisms in skeletal muscle performance

The results of 111 were important in demonstrating that the reduction in the whole-body oxygen cost of exercise following nitrate supplementation is consequent to changes in muscle energy metabolism. The proportional sparing of equation M43 and PCr reported by 111 indicated that nitrate supplementation may alter the energy (adenosine triphosphate [ATP]) cost of muscle power production. The authors suggested that this could occur by the possible effects of NO on the sarcoplasmic reticulum calcium (Ca2+) ATPase or the actin-myosin ATPase 124 125. A lower ATP cost of force production would blunt the changes in intramuscular substrates and metabolites that stimulate mitochondrial respiration (e.g. PCr, ADP, Pi126 ,127. and could explain the lower oxygen cost of exercise. Interestingly, the depletion of muscle PCr and the accumulation of Pi and ADP have been linked with the process of muscle fatigue during high-intensity exercise  128. The blunted changes in energy substrates and metabolites might therefore help to explain the improved exercise tolerance observed following nitrate supplementation. An alternative explanation for the coincident reductions in steady-state equation M44 and PCr is that nitrate supplementation simultaneously improves muscle oxygenation (thus sparing muscle PCr) 129  and improves mitochondrial efficiency (thus lowering equation M45).

Evidence for positive effects of nitrate supplementation on both mitochondrial efficiency 120  and muscle contractile function 130  has recently been presented. Filip J Larsen at al. asked 14 healthy volunteers to consume 0.1 mmol/kg BM/day of sodium nitrate or a placebo for 3 days, after which a muscle biopsy was taken and a submaximal exercise test was completed. Following nitrate supplementation, the expression of adenine nucleotide translocase (ANT), a protein involved in mitochondrial proton conductance, was reduced, thus reducing leak respiration and improving the efficiency of oxidative phosphorylation. Nitrate supplementation resulted in a 19 % increase in the mitochondrial P/O ratio (the amount of oxygen consumed per ATP produced), which was closely correlated (r = −0.80) with the reduction in whole-body equation M46 during submaximal cycling. These results indicate that the reduced equation M47 during exercise following nitrate supplementation is related to a reduced leakage/slippage of protons across the inner mitochondrial membrane. The authors speculated that nitrate supplementation might result in an increased inhibition of cytochrome c oxidase by NO 131132 which might be sensed by the cell as mild hypoxia, initiating signaling  mechanisms that result in a downregulation of ANT and improved mitochondrial efficiency. Interestingly, in contrast to 3 days of in vivo nitrate administration, the acute application of nitrite to isolated mitochondria in vitro had no acute effect on the P/O ratio. This finding suggests that several days of nitrate treatment may be required for the induction of changes in the expression of relevant mitochondrial proteins such as ANT.

However, the effects of nitrate supplementation on muscle function may not be confined to the mitochondria. Hernández et al. 130  have reported improvements in muscle Ca2+ handling and contractile function in mice fed sodium nitrate in water for 7 days compared with age-matched controls that received water without added nitrate. In particular, in fast-twitch muscle fibers, nitrate supplementation increased myoplasmic free Ca2+ concentration at stimulation frequencies from 20 to 150 Hz, effects that were related to the increased expression of calsequestrin 1 and the dihydropyridine receptor, proteins that are involved in Ca2+ handling. These striking effects on intracellular Ca2+ handling resulted in significantly increased contractile force at 50 Hz or less and a faster rate of force development at 100 Hz stimulation. There were no effects of nitrate supplementation on muscle proteins or contractile force in slow-twitch muscles. The authors concluded that dietary nitrate intake in humans may increase muscle function during normal movement. The results of 130 are consistent with the suggestion of 110 that the effects of nitrate on muscle efficiency may be explained, at least in part, by extramitochondrial mechanisms.

In addition to evoking these intracellular effects, there is recent evidence that nitrate supplementation might also enhance blood flow to contracting muscle. Ferguson et al. 133 fed beetroot juice (or a water placebo) to rats for 5 days, and then measured blood pressure and hind limb muscle blood flow during submaximal treadmill running. Exercising blood pressure and blood [lactate] were significantly lower following nitrate feeding, and there was a striking (38 %) increase in muscle blood flow between nitrate-fed and placebo-fed rats. The greater muscle blood flow was directed preferentially towards hind limb muscles expressing a high fraction of type II muscle fibers. Muscle oxygen delivery was therefore substantially elevated in the low oxidative, highly fatigable fibers, such that oxygen might be considered to be more appropriately distributed across and within the active muscles. This might be expected to reduce substrate-level phosphorylation, improve metabolic control and exercise efficiency, and be advantageous to performance 110. In a subsequent study, the same authors reported that microvascular oxygen pressure fell less rapidly following the onset of electrically evoked contractions of the spinotrapezius muscle of rats fed beetroot juice compared with those fed water 133. This is consistent with a greater oxygen driving pressure across the transition from rest to exercise. Those studies  indicate that nitrate supplementation, which may reduce both the ATP and oxygen cost of muscle contraction 111 ,130 ,120, simultaneously increases muscle oxygen delivery. The net result is a higher ratio of oxygen delivery to oxygen utilization, which would be expected to reduce the muscle metabolic perturbation and be conducive to muscle fatigue resistance.

In conclusion efficacy of nitrate might well depend on factors such as the type of subject, including age, diet, and health and fitness status; the intensity, duration, and nature of the exercise challenge; and the dose applied and duration of the nitrate supplementation regimen.

Adaptive antioxidation during excercise


He F. et al

 

ROS produced by leukocytes (due to activation of NADPH oxidase and enzymes such as xanthine oxidase and cyclooxygenase-2) in response to the action of cytokines released by injured muscle as well as by invading neutrophils not only offer antiseptic defence to the muscle but also result in drastic disturbance of muscle’s redox status 134 ,135,136. ROS release during postexercise recovery may cause a secondary damage to both afflicted and healthy adjacent myofibers (due to oxidation of muscle’s protein and lipid molecules) despite a rise in muscle’s antioxidant reserves 137. Reduced glutathione (GSH) is one of the main antioxidants of muscle and is used to neutralize ROS thereby producing its oxidized form (GSSG), a process that results in marked perturbation of redox status in myofibers 138. It has been suggested that the GSH/GSSG couple functions as a key-controller of important redox-sensitive intracellular signaling pathways that lead to cytokine synthesis and release by the injured muscle to activate immune cell recruitment and adhesion such as nuclear transcription factor kB (NFkB) and mitogen activated protein kinases (MAPK) 139. Recent evidence from our group 138 indicated that by attenuating the decline of GSH/GSSG following extensive muscle damage induced by eccentric exercise through administration of a potent thiol-based antioxidant, that is, N-acetylcysteine (NAC), macrophage infiltration in injured muscle, was reduced by ~30% and this response was accompanied by a blunted activation of proinflammatory cytokines and NF-kB and MAPK signaling. Supplementation of antioxidant vitamins did not affect CD4+, CD8+, naive T cells, NK cells, and proinflammatory cytokines responses following intense eccentric exercise 140. In contrast, in vivo and in vitro studies have shown that alterations of GSH/GSSG status via administration of NAC may result in reduced neutrophil chemotaxis 141and macrophage accumulation 142, by attenuating the NF-κB-dependent proinflammatory cytokine expression and release 143,144 as well as increased lymphocyte numbers and activation by inhibiting their apoptotic rate 145suggesting that immune responses in inflammatory states may be redox-dependent. However, this possibility has not been explored in humans in inflammation induced by muscle-damaging exercise. Elucidation of this possibility will shed light to the mechanisms involved in skeletal muscle trauma and aid in the development of potential treatments for diseases characterized by muscle inflammation. In this study we utilized NAC supplementation to enhance GSH stores during recovery from a very intense eccentric exercise protocol performed on an isokinetic dynamometer. We hypothesized that NAC administration alters immune cell responses following exercise-induced muscle damage.

References

References

1.
Jones B, Hoyne GF. The Role of the Innate and Adaptive Immunity in Exercise Induced Muscle Damage and Repair. J. 2017;08(01). doi:10.4172/2155-9899.1000482
2.
Sciorati C, Clementi E, Manfredi A, Rovere-Querini P. Fat deposition and accumulation in the damaged and inflamed skeletal muscle: cellular and molecular players. Cell Mol Life Sci. 2015;72(11):2135-2156. [PubMed]
3.
Kaspar F, Jelinek HF, Perkins S, Al-Aubaidy HA, deJong B, Butkowski E. Acute-Phase Inflammatory Response to Single-Bout HIIT and Endurance Training: A Comparative Study. M. 2016;2016:1-6. doi:10.1155/2016/5474837
4.
Ganter et al. U. Dual control of C-reactive protein gene expression by interleukin-1 and interleukin-6. EMBO. 1989;8(12):3773-3779. 10.1002/j.1460-2075.1989.tb08554.x” target=”_blank” rel=”noopener noreferrer”>https://onlinelibrary.wiley.com/doi/pdf/10.1002/j.1460-2075.1989.tb08554.x.
5.
Flück M, Hoppeler H. Molecular basis of skeletal muscle plasticity-from gene to form and function. In: Reviews of Physiology, Biochemistry and Pharmacology. Springer Berlin Heidelberg; 0:159-216. doi:10.1007/s10254-002-0004-7
6.
Coffey VG, Zhong Z, Shield A, et al. Early signaling responses to divergent exercise stimuli in skeletal muscle from well-trained humans. T. 2006;20(1):190-192. doi:10.1096/fj.05-4809fje
7.
Adams GR, Hather BM, Baldwin KM, Dudley GA. Skeletal muscle myosin heavy chain composition and resistance training. J. 1993;74(2):911-915. doi:10.1152/jappl.1993.74.2.911
8.
Widrick JJ, Stelzer JE, Shoepe TC, Garner DP. Functional properties of human muscle fibers after  short-term resistance exercise training. A. 2002;283(2):R408-R416. doi:10.1152/ajpregu.00120.2002
9.
Spina RJ, Chi MM, Hopkins MG, Nemeth PM, Lowry OH, Holloszy JO. Mitochondrial enzymes increase in muscle in response to 7-10 days of cycle exercise. J. 1996;80(6):2250-2254. doi:10.1152/jappl.1996.80.6.2250
10.
Green HJ, Helyar R, Ball-Burnett M, Kowalchuk N, Symon S, Farrance B. Metabolic adaptations to training precede changes in muscle mitochondrial capacity. J. 1992;72(2):484-491. doi:10.1152/jappl.1992.72.2.484
11.
Benziane B, Burton TJ, Scanlan B, et al. Divergent cell signaling after short-term intensified endurance training in human skeletal muscle. A. 2008;295(6):E1427-E1438. doi:10.1152/ajpendo.90428.2008
12.
Pilegaard H, Saltin B, Neufer PD. Exercise induces transient transcriptional activation of the PGC-1α gene in human skeletal muscle. The Journal of Physiology. 2003;546(3):851-858. doi:10.1113/jphysiol.2002.034850
13.
Mahoney DJ, Parise G, Melov S, Safdar A, Tarnopolsky MA. Analysis of global mRNA expression in human skeletal muscle during recovery from endurance exercise. T. 2005;19(11):1498-1500. doi:10.1096/fj.04-3149fje
14.
Coffey VG, Shield A, Canny BJ, Carey KA, Cameron-Smith D, Hawley JA. Interaction of contractile activity and training history on mRNA abundance in skeletal muscle from trained athletes. A. 2006;290(5):E849-E855. doi:10.1152/ajpendo.00299.2005
15.
Louis E, Raue U, Yang Y, Jemiolo B, Trappe S. Time course of proteolytic, cytokine, and myostatin gene expression after acute exercise in human skeletal muscle. J. 2007;103(5):1744-1751. doi:10.1152/japplphysiol.00679.2007
16.
Yu M, Blomstrand E, Chibalin AV, Krook A, Zierath JR. Marathon running increases ERK1/2 and p38 MAP kinase signalling to downstream targets in human skeletal muscle. The Journal of Physiology. 2001;536(1):273-282. doi:10.1111/j.1469-7793.2001.00273.x
17.
McGee SL, Fairlie E, Garnham AP, Hargreaves M. Exercise-induced histone modifications in human skeletal muscle. The Journal of Physiology. 2009;587(24):5951-5958. doi:10.1113/jphysiol.2009.181065
18.
BAAR K, WENDE AR, JONES TE, et al. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. T. 2002;16(14):1879-1886. doi:10.1096/fj.02-0367com
19.
Wright DC, Han D-H, Garcia-Roves PM, Geiger PC, Jones TE, Holloszy JO. Exercise-induced Mitochondrial Biogenesis Begins before the Increase in Muscle PGC-1α Expression. J. 2006;282(1):194-199. doi:10.1074/jbc.m606116200
20.
McGee SL, Hargreaves M. Exercise and Myocyte Enhancer Factor 2 Regulation in Human Skeletal Muscle. D. 2004;53(5):1208-1214. doi:10.2337/diabetes.53.5.1208
21.
Little JP, Safdar A, Bishop D, Tarnopolsky MA, Gibala MJ. An acute bout of high-intensity interval training increases the nuclear abundance of PGC-1α and activates mitochondrial biogenesis in human skeletal muscle. A. 2011;300(6):R1303-R1310. doi:10.1152/ajpregu.00538.2010
22.
Safdar A, Little JP, Stokl AJ, Hettinga BP, Akhtar M, Tarnopolsky MA. Exercise Increases Mitochondrial PGC-1α Content and Promotes Nuclear-Mitochondrial Cross-talk to Coordinate Mitochondrial Biogenesis. J. 2011;286(12):10605-10617. doi:10.1074/jbc.m110.211466
23.
Barrès R, Yan J, Egan B, et al. Acute Exercise Remodels Promoter Methylation in Human Skeletal Muscle. C. 2012;15(3):405-411. doi:10.1016/j.cmet.2012.01.001
24.
Perry CGR, Lally J, Holloway GP, Heigenhauser GJF, Bonen A, Spriet LL. Repeated transient mRNA bursts precede increases in transcriptional and mitochondrial proteins during training in human skeletal muscle. The Journal of Physiology. 2010;588(23):4795-4810. doi:10.1113/jphysiol.2010.199448
25.
Calabrese EJ, Baldwin LA. Defining hormesis. H. 2002;21(2):91-97. doi:10.1191/0960327102ht217oa
26.
Holloszy JO, Coyle EF. Adaptations of skeletal muscle to endurance exercise and their metabolic consequences. J. 1984;56(4):831-838. doi:10.1152/jappl.1984.56.4.831
27.
Booth FW, Thomason DB. Molecular and cellular adaptation of muscle in response to exercise: perspectives of various models. P. 1991;71(2):541-585. doi:10.1152/physrev.1991.71.2.541
28.
Connor M, Naves L, McCleskey E. Contrasting phenotypes of putative proprioceptive and nociceptive trigeminal neurons innervating jaw muscle in rat. Mol Pain. 2005;1:31. [PMC]
29.
Molliver D, Immke D, Fierro L, Paré M, Rice F, McCleskey E. ASIC3, an acid-sensing ion channel, is expressed in metaboreceptive sensory neurons. Mol Pain. 2005;1:35. [PMC]
30.
Staud R, Mokthech M, Price D, Robinson M. Evidence for Sensitized Fatigue Pathways in Patients with Chronic Fatigue Syndrome. Pain. 2015;156(4):750-759. [PMC]
31.
Egan B, Zierath JR. Exercise Metabolism and the Molecular Regulation of Skeletal Muscle Adaptation. C. 2013;17(2):162-184. doi:10.1016/j.cmet.2012.12.012
32.
Borregaard N, Herlin T. Energy Metabolism of Human Neutrophils during Phagocytosis. J Clin Invest. 1982;70(3):550-557. [PMC]
33.
van R, Sluiter W, de W, Roos D, Verhoeven A, Kuijpers T. Mitochondrial Membrane Potential in Human Neutrophils Is Maintained by Complex III Activity in the Absence of Supercomplex Organisation. PLoS One. 2008;3(4):e2013. [PMC]
34.
Walmsley S, Print C, Farahi N, et al. Hypoxia-induced neutrophil survival is mediated by HIF-1α–dependent NF-κB activity. J Exp Med. 2005;201(1):105-115. [PMC]
35.
Peyssonaux C, Johnson R. An unexpected role for hypoxic response: oxygenation and inflammation. Cell Cycle. 2004;3(2):168-171. [PubMed]
36.
Guimarães TT, Terra R, Dutra PML. Chronic effects of exhausting exercise and overtraining on the immune response: Th1 and Th2 profile. m. 2017;13(3):69. doi:10.6063/motricidade.10049
37.
KA B. Overtraining, Exercise, and Adrenal Insufficiency. J. 2013;03(01). doi:10.4172/2165-7025.1000125
38.
Lacourt T, Vichaya E, Chiu G, Dantzer R, Heijnen C. The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure. Front Behav Neurosci. 2018;12:78. [PMC]
39.
Brinkmann V. Neutrophil Extracellular Traps Kill Bacteria. S. 2004;303(5663):1532-1535. doi:10.1126/science.1092385
40.
Brinkmann V, Zychlinsky A. Beneficial suicide: why neutrophils die to make NETs. N. 2007;5(8):577-582. doi:10.1038/nrmicro1710
41.
Remijsen Q, Kuijpers T, Wirawan E, Lippens S, Vandenabeele P, Vanden B. Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality. Cell Death Differ. 2011;18(4):581-588. [PMC]
42.
Wang Y, Griffiths WJ, Jörnvall H, Agerberth B, Johansson J. Antibacterial peptides in stimulated human granulocytes. European Journal of Biochemistry. 2002;269(2):512-518. doi:10.1046/j.0014-2956.2001.02675.x
43.
Pisetsky D. Pus: the Rodney Dangerfield of immunology. Arthritis Res Ther. 2011;13(5):131. [PMC]
44.
Brinkmann V, Zychlinsky A. Neutrophil extracellular traps: Is immunity the second function of chromatin? J. 2012;198(5):773-783. doi:10.1083/jcb.201203170
45.
Kessenbrock K, Krumbholz M, Schönermarck U, et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med. 2009;15(6):623-625. [PMC]
46.
Fuchs T, Brill A, Duerschmied D, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010;107(36):15880-15885. [PMC]
47.
Garcia-Romo G, Caielli S, Vega B, et al. Netting Neutrophils Are Major Inducers of Type I IFN Production in Pediatric Systemic Lupus Erythematosus. Sci Transl Med. 2011;3(73):73ra20. [PMC]
48.
Lande R, Ganguly D, Facchinetti V, et al. Neutrophils Activate Plasmacytoid Dendritic Cells by Releasing Self-DNA–Peptide Complexes in Systemic Lupus Erythematosus. Sci Transl Med. 2011;3(73):73ra19. [PMC]
49.
Villanueva E, Yalavarthi S, Berthier C, et al. Netting neutrophils induce endothelial damage, infiltrate tissues and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol. 2011;187(1):538-552. [PMC]
50.
Esmon C, Xu J, Lupu F. Innate Immunity and Coagulation. J Thromb Haemost. 2011;9(Suppl 1):182-188. [PMC]
51.
Clarkson P, Dedrick M. Exercise-induced muscle damage, repair, and adaptation in old and young subjects. J Gerontol. 1988;43(4):M91-6. [PubMed]
52.
Byrne C, Twist C, Eston R. Neuromuscular Function After Exercise-Induced Muscle Damage. Sports Med. 2004;34(1):49-69. doi:10.2165/00007256-200434010-00005
53.
Proske U, Morgan D. Muscle damage from eccentric exercise: mechanism, mechanical signs, adaptation and clinical applications. J Physiol. 2001;537(Pt 2):333-345. [PubMed]
54.
Paulsen et al. G. Leucocytes, Cytokines and Satellite Cells: What Role Do They Play in Muscle Damage and Regeneration Following Eccentric Exercise. PDF; 2012:42-97. http://eir-isei.de/2012/eir-2012-042-article.pdf.
55.
Brooks S, Zerba E, Faulkner J. Injury to muscle fibres after single stretches of passive and maximally stimulated muscles in mice. J Physiol. 1995;488 ( Pt 2):459-469. [PubMed]
56.
Paddon-Jones D, Keech A, Lonergan A, Abernethy P. Differential expression of muscle damage in humans following acute fast and slow velocity eccentric exercise. J Sci Med Sport. 2005;8(3):255-263. [PubMed]
57.
Draganidis D, Chatzinikolaou A, Avloniti A, et al. Recovery Kinetics of Knee Flexor and Extensor Strength after a Football Match. Kellermayer MS, ed. PL1. 2015;10(6):e0128072. doi:10.1371/journal.pone.0128072
58.
Nédélec M, McCall A, Carling C, Legall F, Berthoin S, Dupont G. Recovery in Soccer. S. 2012;42(12):997-1015. doi:10.2165/11635270-000000000-00000
59.
Cavassani K, Ishii M, Wen H, et al. TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events. J Exp Med. 2008;205(11):2609-2621. [PubMed]
60.
Malm C, Nyberg P, Engstrom M, et al. Immunological changes in human skeletal muscle and blood after eccentric exercise and multiple biopsies. J Physiol. 2000;529 Pt 1:243-262. [PubMed]
61.
Raastad T, Risoy B, Benestad H, Fjeld J, Hallen J. Temporal relation between leukocyte accumulation in muscles and halted recovery 10-20 h after strength exercise. J Appl Physiol (1985). 2003;95(6):2503-2509. [PubMed]
62.
Chatzinikolaou A, Christoforidis C, Avloniti A, et al. A microcycle of inflammation following a team handball game. J Strength Cond Res. 2014;28(7):1981-1994. [PubMed]
63.
Draganidis D, Chatzinikolaou A, Jamurtas A, et al. The time-frame of acute resistance exercise effects on football skill performance: the impact of exercise intensity. J Sports Sci. 2013;31(7):714-722. [PubMed]
64.
Chatzinikolaou A, Draganidis D, Avloniti A, et al. The microcycle of inflammation and performance changes after a basketball match. J Sports Sci. 2014;32(9):870-882. [PubMed]
65.
Beaton L, Tarnopolsky M, Phillips S. Contraction-induced muscle damage in humans following calcium channel blocker administration. J Physiol. 2002;544(Pt 3):849-859. [PubMed]
66.
Mohr M, Draganidis D, Chatzinikolaou A, et al. Muscle damage, inflammatory, immune and performance responses to three football games in 1 week in competitive male players. Eur J Appl Physiol. 2016;116(1):179-193. [PubMed]
67.
Hubal M, Chen T, Thompson P, Clarkson P. Inflammatory gene changes associated with the repeated-bout effect. Am J Physiol Regul Integr Comp Physiol. 2008;294(5):R1628-37. [PubMed]
68.
Stupka N, Tarnopolsky M, Yardley N, Phillips S. Cellular adaptation to repeated eccentric exercise-induced muscle damage. J Appl Physiol (1985). 2001;91(4):1669-1678. [PubMed]
69.
Raastad T, Owe S, Paulsen G, et al. Changes in calpain activity, muscle structure, and function after eccentric exercise. Med Sci Sports Exerc. 2010;42(1):86-95. [PubMed]
70.
Lauritzen F, Paulsen G, Raastad T, Bergersen L, Owe S. Gross ultrastructural changes and necrotic fiber segments in elbow flexor muscles after maximal voluntary eccentric action in humans. J Appl Physiol (1985). 2009;107(6):1923-1934. [PubMed]
71.
Paulsen G, Crameri R, Benestad H, et al. Time course of leukocyte accumulation in human muscle after eccentric exercise. Med Sci Sports Exerc. 2010;42(1):75-85. [PubMed]
72.
Round J, Jones D, Cambridge G. Cellular infiltrates in human skeletal muscle: exercise induced damage as a model for inflammatory muscle disease? J Neurol Sci. 1987;82(1-3):1-11. [PubMed]
73.
Manfredi T, Fielding R, O’Reilly K, Meredith C, Lee H, Evans W. Plasma creatine kinase activity and exercise-induced muscle damage in older men. Med Sci Sports Exerc. 1991;23(9):1028-1034. [PubMed]
74.
Sorichter S, Puschendorf B, Mair J. Skeletal muscle injury induced by eccentric muscle action: muscle proteins as markers of muscle fiber injury. Exerc Immunol Rev. 1999;5:5-21. [PubMed]
75.
Nosaka K, Clarkson P. Variability in serum creatine kinase response after eccentric exercise of the elbow flexors. Int J Sports Med. 1996;17(2):120-127. [PubMed]
76.
Jones D, Newham D, Round J, Tolfree S. Experimental human muscle damage: morphological changes in relation to other indices of damage. J Physiol. 1986;375:435-448. [PubMed]
77.
Clarkson P, Newham D. Associations between muscle soreness, damage, and fatigue. Adv Exp Med Biol. 1995;384:457-469. [PubMed]
78.
Sayers S, Clarkson P. Force recovery after eccentric exercise in males and females. Eur J Appl Physiol. 2001;84(1-2):122-126. [PubMed]
79.
Foley JM, Jayaraman RC, Prior BM, Pivarnik JM, Meyer RA. MR measurements of muscle damage  and adaptation after eccentric exercise. J. 1999;87(6):2311-2318. doi:10.1152/jappl.1999.87.6.2311
80.
BISHOP et al. PA. RECOVERY FROM TRAINING: A BRIEF REVIEW. Journal of Strength and Conditioning Research. 2008;22(3):1015-1024. http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.473.3392&rep=rep1&type=pdf.
81.
Howatson G, van S. The prevention and treatment of exercise-induced muscle damage. Sports Med. 2008;38(6):483-503. [PubMed]
82.
Connolly et al. DAJ. Treatment and Prevention of Delayed Onset Muscle Soreness. J Strength Cond Res. 2003;17(1):197-208. https://pdfs.semanticscholar.org/7f5a/ea96102e669ec292f9d9114d556d6f928382.pdf.
83.
Cheung et al. K. Delayed Onset Muscle SorenessTreatment Strategies and Performance Factors. Sports Med. 2003;33(2):145-134. https://www.researchgate.net/publication/8075169_Delayed_onset_muscle_soreness_Treatment_strategies_and_performance_factors.
84.
Sakelliou A, Fatouros IG, Athanailidis I, et al. Evidence of a Redox-Dependent Regulation of Immune Responses to Exercise-Induced Inflammation. O. 2016;2016:1-19. doi:10.1155/2016/2840643
85.
Gomez-Cabrera M-C, Domenech E, Romagnoli M, et al. Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance. The American Journal of Clinical Nutrition. 2008;87(1):142-149. doi:10.1093/ajcn/87.1.142
86.
Bryant AE, Aldape MJ, Bayer CR, et al. Effects of delayed NSAID administration after experimental eccentric contraction injury – A cellular and proteomics study. Alway SE, ed. P. 2017;12(2):e0172486. doi:10.1371/journal.pone.0172486
87.
Clarkson P, Nosaka K, Braun B. Muscle function after exercise-induced muscle damage and rapid adaptation. Med Sci Sports Exerc. 1992;24(5):512-520. [PubMed]
88.
CHAPMAN DW, NEWTON M, MCGUIGAN M, NOSAKA K. Effect of Lengthening Contraction Velocity on Muscle Damage of the Elbow Flexors. M. 2008;40(5):926-933. doi:10.1249/mss.0b013e318168c82d
89.
Nosaka K, Clarkson P. Variability in Serum Creatine Kinase Response After Eccentric Exercise of the Elbow Flexors. I. 1996;17(02):120-127. doi:10.1055/s-2007-972819
90.
Chen TC. Variability in Muscle Damage After Eccentric Exercise and the Repeated Bout Effect. R. 2006;77(3):362-371. doi:10.1080/02701367.2006.10599370
91.
HUBAL MJ, RUBINSTEIN SR, CLARKSON PM. Mechanisms of Variability in Strength Loss after Muscle-Lengthening Actions. M. 2007;39(3):461-468. doi:10.1249/01.mss.0000247007.19127.da
92.
SAYERS S, KNIGHT C, CLARKSON P. Neuromuscular variables affecting the magnitude of force loss after eccentric exercise. J. 2003;21(5):403-410. doi:10.1080/0264041031000071146
93.
Chapman D, Newton M, Sacco P, Nosaka K. Greater Muscle Damage Induced by Fast Versus Slow Velocity Eccentric Exercise. I. 2006;27(8):591-598. doi:10.1055/s-2005-865920
94.
Lavender AP, Nosaka K. Responses of old men to repeated bouts of eccentric exercise of the elbow flexors in comparison with young men. E. 2006;97(5):619-626. doi:10.1007/s00421-006-0224-7
95.
Zalavras A, Fatouros IG, Deli CK, et al. Age-Related Responses in Circulating Markers of Redox Status in Healthy Adolescents and Adults during the Course of a Training Macrocycle. O. 2015;2015:1-17. doi:10.1155/2015/283921
96.
McHugh M. Recent advances in the understanding of the repeated bout effect: the protective effect against muscle damage from a single bout of eccentric exercise. Scand J Med Sci Sports. 2003;13(2):88-97. [PubMed]
97.
Kyriazis G. Effects of Plyometric Exercise on Muscle Soreness and Plasma Creatine Kinase Levels and Its Comparison with Eccentric and Concentric Exercise Effects of Plyometric Exercise on Muscle Soreness and Plasma Creatine Kinase Levels and Its. Journal of Strength and Conditioning Research. 2000;14(1):68-74. https://journals.lww.com/nsca-jscr/Abstract/2000/02000/Effects_of_Plyometric_Exercise_on_Muscle_Soreness.12.aspx.
98.
Clarkson P, Hubal M. Are women less susceptible to exercise-induced muscle damage? Curr Opin Clin Nutr Metab Care. 2001;4(6):527-531. [PubMed]
99.
Sayers SP, Clarkson PM. Force recovery after eccentric exercise in males and females. E. 2001;84(1-2):122-126. doi:10.1007/s004210000346
100.
Yamin C, Duarte JAR, Oliveira JMF, et al. IL6 (-174) and TNFA (-308) promoter polymorphisms are associated with systemic creatine kinase response to eccentric exercise. E. 2008;104(3):579-586. doi:10.1007/s00421-008-0728-4
101.
Hubal MJ, Devaney JM, Hoffman EP, et al. CCL2 and CCR2 polymorphisms are associated with markers of exercise-induced skeletal muscle damage. J. 2010;108(6):1651-1658. doi:10.1152/japplphysiol.00361.2009
102.
Appell H, Soares J, Duarte J. Exercise, muscle damage and fatigue. Sports Med. 1992;13(2):108-115. [PubMed]
103.
Falvo MJ, Bloomer RJ. Review of Exercise-Induced Muscle Injury: Relevance for Athletic Populations. R. 2006;14(1):65-82. doi:10.1080/15438620500528380
104.
Gibala M, Interisano S, Tarnopolsky M, et al. Myofibrillar disruption following acute concentric and eccentric resistance exercise in strength-trained men. Can J Physiol Pharmacol. 2000;78(8):656-661. [PubMed]
105.
CHEN C-H, NOSAKA K, CHEN H-L, LIN M-J, TSENG K-W, CHEN TC. Effects of Flexibility Training on Eccentric Exercise-Induced Muscle Damage. M. 2011;43(3):491-500. doi:10.1249/mss.0b013e3181f315ad
106.
NIKOLAIDIS MG, PASCHALIS V, GIAKAS G, et al. Decreased Blood Oxidative Stress after Repeated Muscle-Damaging Exercise. M. 2007;39(7):1080-1089. doi:10.1249/mss.0b013e31804ca10c
107.
Tidball JG, Villalta SA. Regulatory interactions between muscle and the immune system during muscle regeneration. A. 2010;298(5):R1173-R1187. doi:10.1152/ajpregu.00735.2009
108.
Pizza FX, Davis BH, Henrickson SD, et al. Adaptation to eccentric exercise: effect on CD64 and CD11b/CD18 expression. J. 1996;80(1):47-55. doi:10.1152/jappl.1996.80.1.47
109.
Pizza FX, Baylies H, Mitchell JB. Adaptation to Eccentric Exercise: Neutrophils and E-selectin During Early Recovery. C. 2001;26(3):245-253. doi:10.1139/h01-015
110.
Bailey SJ, Winyard P, Vanhatalo A, et al. Dietary nitrate supplementation reduces the O2 cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans. J. 2009;107(4):1144-1155. doi:10.1152/japplphysiol.00722.2009
111.
Bailey SJ, Fulford J, Vanhatalo A, et al. Dietary nitrate supplementation enhances muscle contractile efficiency during knee-extensor exercise in humans. J. 2010;109(1):135-148. doi:10.1152/japplphysiol.00046.2010
112.
Jones A. Dietary Nitrate Supplementation and Exercise Performance. Sports Med. 2014;44(Suppl 1):35-45. [PMC]
113.
Kenjale AA, Ham KL, Stabler T, et al. Dietary nitrate supplementation enhances exercise performance in peripheral arterial disease. J. 2011;110(6):1582-1591. doi:10.1152/japplphysiol.00071.2011
114.
Lansley KE, Winyard PG, Fulford J, et al. Dietary nitrate supplementation reduces the O2 cost of walking and running: a placebo-controlled study. J. 2011;110(3):591-600. doi:10.1152/japplphysiol.01070.2010
115.
Murphy M, Eliot K, Heuertz RM, Weiss E. Whole Beetroot Consumption Acutely Improves Running Performance. J. 2012;112(4):548-552. doi:10.1016/j.jand.2011.12.002
116.
Wylie LJ, Mohr M, Krustrup P, et al. Dietary nitrate supplementation improves team sport-specific intense intermittent exercise performance. E. 2013;113(7):1673-1684. doi:10.1007/s00421-013-2589-8
117.
Wilkerson DP, Hayward GM, Bailey SJ, Vanhatalo A, Blackwell JR, Jones AM. Influence of acute dietary nitrate supplementation on 50 mile time trial performance in well-trained cyclists. E. 2012;112(12):4127-4134. doi:10.1007/s00421-012-2397-6
118.
Christensen PM, Nyberg M, Bangsbo J. Influence of nitrate supplementation on VO2kinetics and endurance of elite cyclists. S. 2012;23(1):e21-e31. doi:10.1111/sms.12005
119.
Vanhatalo A, Bailey SJ, Blackwell JR, et al. Acute and chronic effects of dietary nitrate supplementation on blood pressure and the physiological responses to moderate-intensity and incremental exercise. A. 2010;299(4):R1121-R1131. doi:10.1152/ajpregu.00206.2010
120.
Larsen FJ, Schiffer TA, Borniquel S, et al. Dietary Inorganic Nitrate Improves Mitochondrial Efficiency in Humans. C. 2011;13(2):149-159. doi:10.1016/j.cmet.2011.01.004
121.
Hernández A, Schiffer TA, Ivarsson N, et al. Dietary nitrate increases tetanic [Ca2+]iand contractile force in mouse fast-twitch muscle. The Journal of Physiology. 2012;590(15):3575-3583. doi:10.1113/jphysiol.2012.232777
122.
Bond H, Morton L, Braakhuis A. Dietary nitrate supplementation improves rowing performance in well-trained rowers. Int J Sport Nutr Exerc Metab. 2012;22(4):251-256. [PubMed]
123.
BESCÓS R, FERRER-ROCA V, GALILEA PA, et al. Sodium Nitrate Supplementation Does Not Enhance Performance of Endurance Athletes. M. 2012;44(12):2400-2409. doi:10.1249/mss.0b013e3182687e5c
124.
Evangelista AM, Rao VS, Filo AR, et al. Direct Regulation of Striated Muscle Myosins by Nitric Oxide and Endogenous Nitrosothiols. Agarwal S, ed. P. 2010;5(6):e11209. doi:10.1371/journal.pone.0011209
125.
Viner RI, Williams TD, Schöneich C. Nitric oxide-dependent modification of the sarcoplasmic reticulum Ca-ATPase: localization of cysteine target sites. F. 2000;29(6):489-496. doi:10.1016/s0891-5849(00)00325-7
126.
First-order kinetics of muscle oxygen consumption, and an equivalent proportionality between QO2 and phosphorylcreatine level. Implications for the control of respiration. J Gen Physiol. 1985;86(1):135-165. [PMC]
127.
Meyer R. Linear dependence of muscle phosphocreatine kinetics on total creatine content. Am J Physiol. 1989;257(6 Pt 1):C1149-57. [PubMed]
128.
Allen DG, Lamb GD, Westerblad H. Skeletal Muscle Fatigue: Cellular Mechanisms. P. 2008;88(1):287-332. doi:10.1152/physrev.00015.2007
129.
Wilson D. Factors affecting the rate and energetics of mitochondrial oxidative phosphorylation. Med Sci Sports Exerc. 1994;26(1):37-43. [PubMed]
130.
Hernández A, Schiffer T, Ivarsson N, et al. Dietary nitrate increases tetanic [Ca2+]i and contractile force in mouse fast-twitch muscle. J Physiol. 2012;590(Pt 15):3575-3583. [PMC]
131.
Brown et al. GC. Nanomolar  concentrations of  nitric  oxide  reversibly  inhibit  synaptosomal  respiration  by  competing  with  oxygen  at  cytochrome  oxidase . FEBS. 1994;356:295-298. 10.1016/0014-5793%2894%2901290-3″ target=”_blank” rel=”noopener noreferrer”>https://febs.onlinelibrary.wiley.com/doi/epdf/10.1016/0014-5793%2894%2901290-3.
132.
Cleeter et al. NWJ. Reversible  inhibition  of  cytochrome  c oxidase,  the  terminal  enzyme  of  the mitochondrial  respiratory  chain,  by  nitric  oxide. FEBS. 1994;345:50-54. 10.1016/0014-5793%2894%2901290-3″ target=”_blank” rel=”noopener noreferrer”>https://febs.onlinelibrary.wiley.com/doi/epdf/10.1016/0014-5793%2894%2901290-3.
133.
Ferguson S, Hirai D, Copp S, et al. Effects of nitrate supplementation via beetroot juice on contracting rat skeletal muscle microvascular oxygen pressure dynamics. Respir Physiol Neurobiol. 2013;187(3):250-255. [PMC]
134.
Gomez-Cabrera M-C, Borrás C, Pallardó FV, Sastre J, Ji LL, Viña J. Decreasing xanthine oxidase-mediated oxidative stress prevents useful cellular adaptations to exercise in rats. The Journal of Physiology. 2005;567(1):113-120. doi:10.1113/jphysiol.2004.080564
135.
Nikolaidis MG, Jamurtas AZ, Paschalis V, Fatouros IG, Koutedakis Y, Kouretas D. The Effect of Muscle-Damaging Exercise on Blood and Skeletal Muscle Oxidative Stress. S. 2008;38(7):579-606. doi:10.2165/00007256-200838070-00005
136.
Ji LL. Antioxidant signaling in skeletal muscle: A brief review. E. 2007;42(7):582-593. doi:10.1016/j.exger.2007.03.002
137.
Peake et al. J. Characterization of inflammatory responses to eccentric exercise in humans. EIR. 2005;11:64-85. http://ro.ecu.edu.au/cgi/viewcontent.cgi?article=3979&context=ecuworks.
138.
Michailidis Y, Karagounis LG, Terzis G, et al. Thiol-based antioxidant supplementation alters human skeletal muscle signaling and attenuates its inflammatory response and recovery after intense eccentric exercise. The American Journal of Clinical Nutrition. 2013;98(1):233-245. doi:10.3945/ajcn.112.049163
139.
Zhou LZ-H, Johnson AP, Rando TA. NFκB and AP-1 mediate transcriptional responses to oxidative stress in skeletal muscle cells. F. 2001;31(11):1405-1416. doi:10.1016/s0891-5849(01)00719-5
140.
Petersen EW, Ostrowski K, Ibfelt T, et al. Effect of vitamin supplementation on cytokine response and on muscle damage after strenuous exercise. A. 2001;280(6):C1570-C1575. doi:10.1152/ajpcell.2001.280.6.c1570
141.
Milara J, Juan G, Peiró T, Serrano A, Cortijo J. Neutrophil Activation in Severe, Early-Onset COPD Patients versus Healthy Non-Smoker Subjects in vitro: Effects of Antioxidant Therapy. R. 2012;83(2):147-158. doi:10.1159/000332834
142.
Campos R, Shimizu MHM, Volpini RA, et al. N-acetylcysteine prevents pulmonary edema and acute kidney injury in rats with sepsis submitted to mechanical ventilation. A. 2012;302(7):L640-L650. doi:10.1152/ajplung.00097.2011
143.
Tsai H-H, Lee W-R, Wang P-H, Cheng K-T, Chen Y-C, Shen S-C. Propionibacterium acnes-induced iNOS and COX-2 protein expression via ROS-dependent NF-κB and AP-1 activation in macrophages. J. 2013;69(2):122-131. doi:10.1016/j.jdermsci.2012.10.009
144.
Palacio JR, Markert UR, Martínez P. Anti-inflammatory properties of N-acetylcysteine on lipopolysaccharide-activated macrophages. I. 2011;60(7):695-704. doi:10.1007/s00011-011-0323-8
145.
QUADRILATERO J, HOFFMAN-GOETZ L. N-Acetyl-L-Cysteine Inhibits Exercise-Induced Lymphocyte Apoptotic Protein Alterations. M. 2005;37(1):53-56. doi:10.1249/01.mss.0000149809.95484.3d
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