InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Medicine » Orthopedics, Physical Medicine and Rehabilitation » "Muscle Injuries in Sport Medicine", book edited by Gian Nicola Bisciotti and Cristiano Eirale, ISBN 978-953-51-1198-6, Published: September 11, 2013 under CC BY 3.0 license. © The Author(s).

Chapter 2

Nutritional Interventions as Potential Strategy to Minimize Exercise-Induced Muscle Injuries in Sports

By Giuseppe D’Antona
DOI: 10.5772/56590

Article top

Nutritional Interventions as Potential Strategy to Minimize Exercise-Induced Muscle Injuries in Sports

Giuseppe D’Antona1

1. Introduction

Muscle injury has been related to resistance exercise and prolonged endurance exercise paradigms both leading to significant local mechanical constraints followed by focal disorders such as sarcolemmal damage and leakage of intracellular proteins, oedema, myofibrillar disorganization and microtrauma-triggered inflammation. These unfavorable events lead to variable soreness, swelling, loss in muscle strength and function with reduced range of motion.

To date strategies finalized to minimize exercise-induced muscle injury are scarce and often not adequately supported by research studies.

Based on the notion that dietary supplementations may exert a variety of beneficial effects on the skeletal muscle, in the last 20 years there has been a great deal of interest in nutritional strategies aiming to attenuate signs and symptoms of exercise induced muscle injuries. Anyhow a large number of variables influences the muscular outcome of nutritional supplements, strongly depending on nutrient type, genotype, age, and regulation of nutrient sensing pathways.

Overall there is a paucity of studies on the topic, partly related to the high number of supplements to be considered and their combined use. In general nutrients as vitamins (as vitamin C), N-acetyl-cysteine, L-carnitine, creatine, and branched chain amino acids (BCAA) may exert a potential beneficial role but the underlying cellular mechanism, the optimal dosage and the duration of the pretreatment/treatment period are currently unknown.

This chapter addresses the current knowledge on the potential use of nutritional supplements in preventing and/or minimizing muscle injuries due to resistance or endurance exercise training.

“If the soreness then, be caused by the same conditions which produce fatigue, namely the presence of diffusible waste products of activity we should expect to find, as we do find, that it takes the course described above, passing away within few hours of the work itself” [1]

In 1900 Theodore Hugh first described that exercise induced muscle injury is not a fatigue phenomenon but the consequence of mechanical overload followed by structural and functional muscular changes [1].

Cycles of repetitive eccentric and concentric contractions represent a fundamental source of mechanical stress for active skeletal muscle and vulnerability of skeletal muscle fibers appears to be particularly evident in unaccustomed individuals. In fact conditioning of the muscle through prior similar activity may minimize damage appearance (so called “repeated bout effect”) [2]. Overall the process appears as a fundamental step for the arising of exercise-induced plastic response as it is followed by muscle remodeling and adaptation [3]. However muscle damage may delay muscle recovery from exercise and performance thus reducing the athletes compliance to exercise programmes.

The direct consequence of mechanical stress on active skeletal muscle fibers is the appearance of soreness (delayed onset muscle soreness, DOMS), stiffness and reduced force production. This is particularly the case as a consequence of strenuous physical work involving heavy resistance exercise including eccentric (i.e. lengthening) actions [4-6]. In these conditions force loss appears immediately post-exercise whereas soreness becomes evident within 24-48 hours after and, as the force impairment, may last several days depending of the extent of damage [7]. At the microscopic and submicroscopic level fibers damage, which preferentially involves fast twitch fibers [8], is already evident within minutes from the mechanical insult [9] displays throughout individual fibers (i.e. focal injury), and includes plasma membrane disruption accompanied by the loss of muscle proteins in the serum (i.e. creatine kinase (CK), myoglobin, lactate dehydrogenase (LDH), aldolase, troponin), myofibrillar disorders as streaming and broadening of the Z-lines, loss of sarcomeres register, the appearance of regions of overextended sarcomeres, regional disorganization of the myofilaments, subsarcolemmal lipofuscin granules accumulation, alterations of the proteoglycan components, increased interstitial space, and capillary damage [10-15]. Interestingly dramatic changes in the organization of the membrane systems involved in excitation-contraction coupling have been also found following eccentric contractions [16]. The most commonly identified alterations include disorders of the T tubule, changes in the direction and spatial orientation of the triads, and the appearance of caveolar clusters, pentads and heptads (close apposition of two or three T tubule elements with three or four elements with three or four elements of terminal cisternae of sarcoplasmic reticulum).

Apart mechanical stress, other mechanisms may contribute to muscle damage. In particular a metabolic impairment has been proposed as a result of ischemia or hypoxia during prolonged and intense resistance exercise. This insult leads to changes in ion concentration, accumulation of metabolic wastes, and adenosine triphosphate (ATP) deficiency which contribute to soreness and impaired function.

Importantly the early mechanical and metabolic mechanisms can promote biochemical changes within the affected area, leading to the generation of a secondary muscle damage including disruption of intracellular calcium homeostasis, local accumulation of inflammatory cytokines such as tumor necrosis factor-a, interleukin (IL)-1b, IL-6, and IL-1 receptor antagonist (IL-1ra) [17], de facto mimicking the sequential release of cytokines after trauma [18], and reactive oxygen species (ROS) that may further degrade muscle proteins and increase the local expression of cytokines [19, 20]. This condition may contribute to persistence of signs and symptoms of injury.

Although it is widely accepted that high intensity eccentric exercise is the fundamental exercise paradigm resulting in muscle damage and subsequent adaptation, structural and functional damage may also arise following long lasting endurance exercise paradigms as demonstrated by the appearance of ultrastructural alterations, as fibers necrosis, sarcolemmal disruption, Z discs streaming, contracture knots, and inflammatory infiltration in endurance athletes even before a race [21]. Anyhow even though the extent and location of damage may greatly vary according to the exercise paradigm and the previous conditioning of the muscoloskeletal system, the extent of damage observed with low intensity and long duration endurance exercise is often less pronounced than with higher intensities. This is the main reason of why most of works finalized to the identification of the physiological mechanisms that regulate the response to exercise-induced stress in skeletal muscle and the possible countermeasures, including the approach based on nutrient supplementation, have been focused on strength training exercise.

2. Nutritional intervention to minimize exercise-induced muscle injury

For decades, dietary supplementation has been proposed in various physiological or pathological conditions. Based on the recent progress in our understanding of the cell signaling and in vivo metabolism of nutrients and on accumulating experimental results, the concept that dietary supplementation might have effects in prevention or treatment of several disorders is experiencing a new revival. To date several investigations have been focused on accumulating experimental evidence aiming to extend the use of specific nutritional supplements in the prevention and/or treatment of exercise induced muscle injuries. Anyhow available outcomes on potentially efficacious supplements are mixed and often conflicting and confident conclusions cannot be drawn. Several variables may concur to contradictory results including the wide number of supplements to be considered, their combined use, their dose and timing of administration. Furthermore the choice of the proper indexes to be analyzed is certainly a major bias for several published studies on the topic as a misinterpretation of results may follow the analysis of indirect instead of direct signs of muscle injury. Thus, although many nutrients are potentially able to impact on the mechanisms underlying the appearance of muscle damage following exercise, the final efficacy and safety of their supplementation deserves future rigorous investigation.

The present chapter discusses the potential role of antioxidants, creatine, carnitine and branched chain amino acids on exercise induced muscle damage.

3. Antioxidant/vitamines

Nutritional antioxidants are non enzymatic compounds including the lipid-soluble vitamin E, β-carotene, co-enzyme Q10 (CoQ), and the water-soluble vitamin C, glutathione, and uric acid. These antioxidants either scavenge ROS into less reactive molecules or prevent their transformation into more highly reactive forms, having intracellular and extracellular sites of action [22].

During exercise and exercise-induced damage whole body oxygen consumption increases up to 20 fold and ROS are generated in excess [23]. The primary sources of ROS are endogenous sites within the skeletal muscle, whereas the secondary sites of production are exogenous [24]. Within the muscle the main font of ROS is reputedly through electron leakage in the mitochondria during mitochondrial phosphorylation and via xanthine oxidase metabolism in the capillary endothelium [25, 26] whereas the main secondary source of ROS is generated during the inflammation mainly by neutrophils.

Considering that increased ROS production could challenge the natural antioxidant defense system and that ROS play a major role in the initiation and progression of exercise-induced skeletal muscle injury [27, 28], it has been hypothesized that antioxidants supplementation may minimize its extent and this topic has been faced by a plethora of studies. However, to date, strong evidence to support significant reductions in structural or functional impairment due to antioxidants is missing. Inconsistencies of findings may relate to ununiformities in the experimental designs in terms of type, dose, time of administration and chosen indexes to evaluate and quantify muscle injury. In fact the majority of investigations have been focused on the effects of vitamin C and E and looked at changes in plasma concentrations in CK and LDH and oxidative stress markers. Much less studies have analyzed direct indexes of muscle damage as loss in muscle strength, soreness and structural/ultrastructural changes of the fibers [26, 29]. Indeed a not univocal strategy in the timing of supplementation (pre exercise, during exercise, post exercise) has been adopted demonstrating de facto a lack of a univocal and definite and generally accepted mechanism underlying the correlation between exercise, muscle damage, and antioxidant activity. As a matter of facts several studies have examined the effects of antioxidants on indices of ROS-induced muscle damage in exercise and suggested that antioxidant supplementation may exert some protection particularly in relation to bouts of resistance exercise in untrained or physically active individuals [30-35] as demonstrated by a reduced inflammation [35-39], force loss [30, 40, 41], and fatigue appearance [42, 43] and no evidence for any beneficial effect on performance [44]. On the contrary no significant effects of antioxidant supplements have been found by other authors on indices of inflammation [45-49], cell damage [45, 48, 50-53], oxidative stress [53], and muscle soreness [54-57]. The lack of effects appears to be particularly evident in highly trained individuals whose adaptation to increased exposure to oxidation is normally able to promote a secondary increase of the endogenous antioxidant defenses that reduce the risk of oxidative damage [58, 59] Therefore even following extreme exercise paradigms, unlike short periods of modest exercise [60], indications of oxidative damage may lack in well trained athletes [61]. Importantly in these conditions exposure to antioxidants may hinder the beneficial cell adaptations to exercise thereby promoting muscle damage instead of recovering from it [55, 62-64]. In fact there are concerns about possible adverse effects of megadose supplementation, as several of these nutrients have been shown to increase markers of exercise-induced oxidative stress thus serving as prooxidants instead of antioxidant nutrients. For example after intense exercise, supplementation with vitamin C, vitamin E, N-acetylcysteine and coenzyme Q10 was associated with oxidative stress, increased serum CK and, in some cases, reduced performance [63-67]. In another study prolonged (2 months) vitamin E supplementation increased lipid peroxidation and inflammation [68] whilst no effects on resting levels of oxidative stress were observed by others following vitamin C and E supplementation in ultraendurance athletes [69].

Vitamin C. To date there is no evidence to support the hypothesis that acute and prolonged supplementation with ascorbic acid before and/or after exercise may prevent/attenuate exercise induced muscle damage.

Although a long lasting supplementation with vitamin C before exercise bouts has met with conflicting results, some of them reporting a beneficial effect on lipid peroxidation and inflammation [70] probably due to an increase of the baseline response of antioxidant enzymes [71], nowhere a clear effect on muscle damage has been reported. Similar results have been obtained following acute supplementation prior to exercise. In particular an early study by Ashton and colleagues [72] demonstrated a protective effect of an acute dose of ascorbic acid against ROS production following exhaustive exercise. In this study no indices of muscle damage were measured. Later the effects of an identical dose of ascorbic acid 2 hours before 90 minutes of intermittent shuttle running were investigated by others [52]. Supplementation did not affect the increases in serum CK, serum aspartate aminotransferase, and delayed onset muscle soreness [52]. Importantly the same negative results were obtained when supplementation was performed after training. In particular vitamin C supplementation for 3 days after an intermittent shuttle running showed no effects on indexes of muscle damage, lipid peroxidation and inflammatory response [56]. In another study combination of vitamin C with n-acetylcysteine for 7 days after an eccentric bout of exercise exerted a prooxidant effect. Furthermore equivocal results emerged when supplementation was given before and after exercise bouts, as the smoothening effects on DOMS observed by some authors [34, 73] have been not confirmed by others [54, 55].

Overall, although conflicting results on the topic may result from ununiformities of supplementation strategies and inconsistencies in the experimental procedures adopted (for example the lack of crossover design or the missing measures of direct indexes of muscle damage), there is limited evidence of a protective effect of vitamin C on exercise induced muscle damage.

Vitamin E. Vitamin E, the most important lipid-soluble antioxidant vitamin, is known to stop the progression of the lipid peroxidation chain reaction and is an important scavenger of the superoxide, hydroxyl and lipid peroxyl radicals [74]. Vitamin E can be recycled from its radical form by vitamin C and less efficiently by other antioxidants (glutathione, CoQ, cysteine and a-lipoic acid). Importantly, this vitamin may also act as a prooxidant in the absence of these antioxidants [75]. Most of studies investigating the effects of vitamin E on exercise induced muscle damage have utilized a preexercise supplementation strategy starting from the assumption that vitamin E, contrarily to vitamin C, being lipid-soluble can be stored in tissues. Anyhow direct indexes of muscle damage were not adequately measured in most cases and available results, albeit suggesting a minimal, unless absent [45], protection of vitamin E supplementation on oxidation, membrane damage [76, 77], and inflammation [76], do not provide enough evidence for a protective effect of vitamin E on exercise induced muscle damage.

In conclusion, there is little evidence to support the suggestion that supplementation with antioxidant nutrients can improve exercise performance, but there is a growing body of evidence to suggest that supplementation may reduce the extent of exercise induced oxidative damage. If this is indeed the case, it may be that the athlete undertaking a strenuous training programme may benefit in the long term by being able to sustain a higher training load (less fatigue). There is also evidence, however, that prolonged exposure to training increases the effectiveness of the endogenous antioxidant mechanisms, and it may be that supplementation is unnecessary or prooxidant and thus potentially unsafe.

4. Carnitine

Carnitine is the required carrier of fatty acids from the cytoplasm into mitochondria, where they undergo β-oxidation [78, 79]. In the cytoplasm carnitine combines with fatty acyl-coenzyme A (acyl-CoA) thus allowing that fatty acids may enter the mitochondrion. The first step of this process is catalysed by carnitine palmitoyl transferase 1 (CPT1) and the trans-membrane transport is facilitated by acylcarnitine transferase. Within the mitochondrion free carnitine is regenerated by the action of carnitine palmitoyl transferase 2 (CPT2) and the released fatty acyl-CoAs entry the β-oxidation pathway. Within the mitochondrion, carnitine also regulats the acetyl-CoA concentration and the concentration of free CoA. Considering that free CoA is involved in the pyruvate dehydrogenase reaction and in the process of β-oxidation it contributes to the coordinated integration of fat and carbohydrate metabolism. In fact when glucose oxidation increases, acetyl groups can be translocated from acyl-CoA within the mitochondrial matrix to the cytoplasm. The accumulation of cytosolic acetylcarnitine may result in a limitation of CPT-1 activity because of the decrease in availability of free carnitine. Consequently, there is fatty acid oxidation, since skeletal muscle predominantly expresses an isoform of CPT-1 with low affinity for L-carnitine [80].

In humans, 75% of carnitine is obtained from the diet. The primary dietary sources of carnitine are red meat and dairy products [81]. Dietary carnitine is absorbed from the intestinal lumen across the mucosal membrane by both passive and active transport mechanisms. Carnitine is also synthesized in the liver and in the kidneys (not in skeletal and cardiac muscle) [82] from the essential amino acids, lysine and methionine [83, 84] having ascorbic acid, ferrous iron, pyroxidine, and niacin as necessary cofactors [85]. More than 95% of the body’s total carnitine store is within skeletal muscle tissue [86], and decreased plasma carnitine level has been related to low tissue concentrations [79, 87].

Considering the key roles of carnitine for normal skeletal muscle bioenergetics (long-chain fatty acid oxidation; removal of acyl groups from the mitochondria; detoxification), its availability may be the limiting factor for fatty acid oxidation and/or the removal of acyl-CoAs also during exercise [82]. Based on such considerations it has been proposed that carnitine consumption may improve exercise performance and/or recovery from exercise. Consistently the large majority of studies observed a beneficial effect of L-carnitine supplementation on maximum oxygen uptake or respiratory quotient in healthy athletes [88] whereas only a minority of studies failed to observe such effects [88]. In particular, several scientific reports highlight that carnitine supplement could be an ergogenic aid for endurance exercise [89, 90] as in presence of concomitant low carnitine concentration in skeletal muscle limiting carnitine acyltransferases to operate at a high rate, the oral ingestion of carnitine would result in an increase of the total carnitine concentration. This effect may be followed by increased rate of oxidation of intramuscular fatty acids and triacylglycerols during exercise thus reducing muscle glycogen breakdown and postponing fatigue appearance [88]. On the other hand a decrease of free carnitine concentration to very low levels is expected in skeletal muscles subjected to high-intensity training because the compound tends to react with acetyl- CoA. This decrease has been suggested as one of the mechanisms for the reduction of plasma fatty acid and intramuscular triacylglycerol oxidation during high-intensity exercise [91]. Accordingly most studies showed improved maximum oxygen consumption, reduced lactate accumulation, and increased high-intensity exercise performance in professional and nonprofessional athletes, especially when L-carnitine was supplemented for longer periods and at higher doses [92-95]. However, some investigations failed to show any effect of carnitine supplementation following on high-intensity training programs [96-101].

Recently a discrete bulk of research has provided the evidence to support the theoretical potential for the use of L-carnitine supplementation in exercise recovery. These studies demonstrated that supplemental carnitine is effective in attenuating tissue damage as directly assessed via magnetic resonance imaging, muscle soreness, and postexercise markers of metabolic stress following eccentric exercise training [102] or intense resistance exercise [103-105] thus leading to a quicker recovery (2 to 3 g/day of elemental carnitine being supplied by L-carnitine L-tartrate, LCLT). In particular Volek and colleagues [103] analyzed the effects of L-carnitine (2g/d for 3 wk before exercise and during 4d recovery) on markers of muscle damage in trained adult man following 5 sets of 15-20 repetitions of squats at 50% of 1-RM. Treated subjects experienced reduced muscle damage and decreased circulating CK compared to placebo. Similar results, recently obtained by the same authors, have clearly shown that LCLT is also effective in promoting recovery of tissue damage arising from the same protocol of high-repetition squat exercise in elderly individuals [106].

Overall the observed benefits of L-carnitine supplementation in preventing exercise-induced muscle injury have mostly been attributed to its potential as antioxidant. Increased generation of ROS is considered as a major cause of disruption/damage to the sarcolemma leading to leakage of cytosolic proteins into the circulation (CK, myoglobin, LDH). Furthermore ROS generated beyond physiological limits are found to reduce muscle force production by altering calcium ion sensitivity in muscle and thus contributing to muscle fatigue [107] [108, 109]. L-carnitine supplementation has been related to reduced postexercise CK [102, 103] and myoglobin [103, 105] concentrations suggesting that reduced oxidative stress may play a role in a quicker muscle recovery from strenuous exercise following supplementation. As a matter of fact early studies by Brass et al. (1993) [110] demonstrated that L-carnitine delays hypoxia-induced fatigue in electrically stimulated rat skeletal muscle in vitro through its key stimulatory role in muscle bioenergetics and antioxidant activity. Further evidence demonstrated that L-carnitine exhibits effective superoxide anion radical and hydrogen peroxide scavenging, total reducing power and metal chelating activities in vitro [111]. In vivo, in presence of high glycolytic rates as during strenuous resistance exercise, the stimulated formation of ATP and AMP from molecules of ADP results in the oxidation of AMP to hypoxanthine which is considered a marker of metabolic stress [112]. This oxidation reaction is mediated by xanthine oxidase. Accumulation of xanthine oxidase in spite of xanthine dehydrogenase is the consequence of the activation of calcium-dependent proteases, which cleave a portion of xanthine dehydrogenase and convert it into xanthine oxidase. This process is a direct consequence of raised intracellular calcium by inhibition of calcium ATPase pumps induced by insufficient supply of ATP. This response appears to be attenuated by L-carnitine supplementation which reduces intracellular hypoxanthine and xanthine oxidase following resistance exercise bouts [103, 106]. Indeed inhibition of xanthine oxidase with allopurinol during exercise has been shown to result in significantly less generation of ROS, reduced tissue damage after exhaustive exercise [112], and less accumulation of cytosolic enzymes CK and LDH [113, 114]. Furthermore a direct consequence of high-intensity training is hypoxia. Exercise under hypoxic conditions stimulates muscle glucose transport, increases the concentration of ammonia in blood, and lowers the concentration of free carnitine [115, 116]. It has been found that carnitine supplementation during exercise under hypoxic conditions may also prevent ammonia toxicity mainly through reduction of ROS production.

In summary, L-carnitine supplementation can beneficially affect postexercise markers of metabolic stress, muscle disruption, and muscle soreness in young and old healthy men and women. The attenuation of the side effects of high-intensity training mainly relate to its antioxidant potential and its capability to reduce the magnitude of exercise-induced hypoxia. Further research is needed to conclusively elucidate the mechanisms underlying its protective effects and whether these responses may also arise in exercised individuals affected by disorders of different origin as neuromuscular diseases.

5. Creatine

A large number of surveys indicate that creatine (n [aminoiminomethyl]-N-methylglycine) is one of the most widely used nutritional supplements [117-122]. Prevalence studies indicate that the use of creatine is particularly common in athletes and soldiers. Among the athletes population, powerlifters, boxers, weightlifters, and track/field athletes report the higher creatine consumption with prevalence ranging between 45 and 75% [122]. The major determinant of such a widespread consumption by resistance athletes mainly resides in the known ergogenic aid of creatine when supplementation is associated with repeated bouts of high intensity exercise. This combination leads to increased lean body mass (with no effect on fat mass), muscle strength and performance and accelerated post-exercise recovery [123]. Interestingly more pronounced effects of creatine supplementation have been found in strength trained older adults compared to the young adults [124] and in untrained compared to trained individuals whereas similar changes in muscle creatine content and exercise performance have been found between men and women [125, 126]. Besides no ergogenic effect of creatine has been found in a variety of endurance exercise paradigms [127-129].

Several mechanisms could explain the effects of creatine supplementation on muscle mass, strength and performance when supplementation is combined with strength training.

The hypertrophic response has been attributed to increased myosin heavy chain protein expression [130], changes in the expression of myogenic regulatory factors (MRF4 and myogenin) [131, 132], increased mitotic activity of satellite cells and swelling-induced protein synthesis [133-137] followed by net protein deposition. The most popular mechanism to explain the efficacy of creatine on muscle performance refers to a better match between ATP supply and fibers demands during physical exercise due to the enhancement of the resting high energy phosphate levels (total creatine, phosphocreatine, creatine and ATP) observed following supplementation. This change allows users to maintain a greater work intensity for longer durations of time (increased total training volume). In particular, the intracellular concentration of phosphocreatine is known to play a major role during the bioenergetic system mostly active during exercise at high intensities and short durations. Overall the dosing regimen that has been found to significantly increase the intracellular phosphocreatine is a loading phase of approximately 20 g/day for 5-7 days followed by a maintenance phase of 5 g/day for a period of several weeks [138, 139].

The known effects of creatine upon muscle cell function, structure and protein metabolism may represent the rationale for its potential use to prevent or treat muscle cell injuries. Nevertheless, although solid studies have examined the ergogenic potential of creatine, the current literature is very preliminary in relation to examining the effects of creatine supplementation in reducing the severity of exercise-induced muscle damage and/or promote recovery following strength training and endurance paradigms [140].

Considering that high-force eccentric exercise alters myofibre membrane structure and function [9, 141] leading to reductions in force, increased soreness, and impaired muscle function and that membrane stabilization due to decreased membrane fluidity is followed to increased intracellular concentration of phosphocreatine [142], the effects of creatine supplementation on markers of eccentric exercise damage have been assessed following resistance exercise sessions [143-146]. Initial studies conducted in rodents and humans agreed to demonstrate that creatine supplementation does not decrease muscle damage or enhance recovery after high intensity eccentric contractions. In particular Warren and colleagues [143] demonstrated that recovery of mouse anterior crural muscle strength after damage induced by 150 eccentric contractions was unaffected by creatine supplementation at 0.5 and 1% for two weeks. Following 3 minutes recovery, there was no effect of creatine supplementation on the isometric torque loss or on the torque loss at any eccentric or concentric angular velocity tested [143]. In 2001 Rowson and colleagues [146] evaluated the effects of short time creatine and dextrose supplementation (20 gr d-1 creatine and 28 gr d-1 for 5 days, a protocol previously shown to be effective in elevating muscle creatine and phosphocreatine levels [126]) before performing 50 maximal eccentric contractions of the elbow flexors on blood markers of muscle damage (CK and LDH), maximal isometric force, range of motion, arm circumference (an index of swelling), and muscle soreness. Despite the initial hypothesis, results showed nearly identical loss of maximal isometric force and range of motion, development of soreness, increase of the biceps circumference and change in blood CK and LDH in supplemented and placebo groups of subjects thus suggesting that creatine supplementation lacked to display significant improvement of membrane stabilization at the conditions analyzed. In a second study by the same authors male participants were supplemented with creatine for 5 days prior to, and 5 days following a hypoxic resistance exercise test (5 sets of 15-20 repetitions at 50% of 1 repetition maximum). Similarly to the first study creatine failed to have positive effects on the same criterion measures of muscle damage following the resistance exercise challenge [145]. More recently differing results have been obtained following creatine and carbohydrate supplementation to untrained male subjects by the scheme 5 days prior to, and 14 days following a resistance exercise training session consisting of 4 sets of 10 eccentric repetitions at 120% of maximum concentric 1-RM on the leg press, leg extension and leg flexion machine. Creatine supplementation produced significantly greater isokinetic and isometric knee extension strength during recovery from exercise-induced muscle damage. Furthermore, plasma CK activity was lower after 48, 72, 96 hrs, and 7 days recovery in the supplemented group [144]. As discussed by Cook such diverse observations could be in part attributed to the duration of supplementation period and/or post-exercise supplementation. In particular in the first study by Rawson the subjects enrolled were supplemented only for 5 days prior to the exercise protocol; with no continuation of supplementation following the exercise bout [146]. As it has been suggested that the effect of creatine on protein synthesis and muscle regeneration may be enhanced during the recovery period post-injury [130, 147], the time schedule of creatine supplementation respect to the exercise bout may be considered a potential limiter of the muscular protection against exercise-induced damage. This hypothesis seems to be confirmed by the observed increase of satellite cell number and myonuclei concentration following creatine supplementation in human skeletal muscle [147]. Indeed it can be hypothesized that this effect may sum to the known training-induced increase in muscle regeneration.

Notwithstanding supplementation was continued for 5 days after the exercise bout, in the second study by Rawson and colleagues no beneficial effects of creatine on criterion measures of muscle damage were observed [145]. Although it cannot be excluded that the resistance exercise paradigm used by Rawson, designed to be hypoxic in nature, may not have elicited enough muscle damage to unmask the anabolic effects of creatine supplementation, to date available conflicting data from a limited number of experimental works on the topic do not allow to safely draw conclusions on the beneficial effects of oral creatine supplementation on skeletal muscle damage and recovery following eccentric exercise challenge and new, more standardized, experimental works would help unravel this question in the next future.

Based on the fact that cell injury in running depends on cell volume integrity and that creatine potentially stabilizes the cell volume through an increase in cell water content, glycogen stores and/or myofibrillar content [135-137, 148], the effect of oral creatine supplementation has also been examined on markers of muscle damage, i.e. inflammatory and muscle soreness markers, following prolonged running exercise (30Km run) [149]. Marathon runners were supplemented for 5 days (20 g/day) prior to a 30km race. Blood samples were collected pre-race, and 24 hours following the end and CK, LDH, prostaglandin E2 (PGE2) and TNFalpha (TNF-α) were measured.

As expected, prolonged running provoked an increase in concentrations of all plasma markers tested, indicating the appearance of cell injury associated with an inflammatory response [6, 150]. Creatine supplementation was effective in significantly attenuate the observed increase in all muscle soreness markers analyzed, unlike CK, thus pointing this nutritional intervention as an effective strategy in maintaining muscle integrity during and after intense and prolonged endurance exercise. In fact the lack of effect upon plasma CK concentration might not reflect the overall positive effect of creatine on muscle damage as a strong variability of this parameter among athletes, its dependence from the training status and the weak correlation with changes in other markers of muscle damage [151-153] lessen its significance in comparison with other markers of cellular death and lysis as LDH [154]. Similar effects on plasma pro inflammatory markers (Interleukin (IL) 1 beta and IL-6, TNF-α, and Interferon alpha (INF alpha) and PGE2) [155] and on plasma markers of cellular integrity (CK, LDH aldolase (ALD), glutamic oxaloacetic, acid transaminase (GOT), glutamic pyruvic acid transaminase (GPT), and C-reactive protein (CRP) [156] have been obtained in double blind trials following creatine supplementation (20gr day-1) 5 days before a half-ironman and after ironman triathlon competition respectively.

These results confirm the hypothesis that creatine may have a protective effect against membrane cell disruption following prolonged and intense muscle contractions [156]. Indeed as skeletal muscle damage during an ironman competition mostly result from eccentric contractions, mainly related to the marathon segment of the race [157], it can be argued that creatine may be effective in preventing eccentric induced muscle injury. In fact exhaustive exercises involving eccentric contractions, as in triathlon competition, lead to more pronounced muscle damage than strenuous exercises involving concentric contractions [158]. Nevertheless other mechanisms but eccentric damage may contribute to muscle damage during triathlon competition including excessive metabolic workload, muscle fatigue, depletion of intramuscular glycogen, and oxidative stress which are generally implicated in prolonged exercise-induced muscle fiber disruption [157, 159, 160]. The observed reduction in plasma activities of GOT and GPT (markers of liver injury) observed in triathletes after an ironman competition may suggest that creatine supplementation can enhance the metabolic efficiency of skeletal muscle preventing the metabolic workload on the liver which has a critical role on the contractile activity-induced skeletal muscle injury. Indeed when eccentric contraction is avoided as in electrically stimulated gastrocnemius muscle of the rat, creatine supplementation has been found to delay the fatigue appearance, preserve the force development, and prevent the rise of LDH and CK plasma activities and muscle vascular permeability evaluated with Evans blu staining [156]. Furthermore, although it cannot be excluded that in endurance settings the benefits of supplementation in preventing muscle damage may relate to the antioxidant potential that has been attributed to creatine in various oxidative stress-associated diseases, few studies have been published on the relationship between supplementation and oxidative stress and controversial and not conclusive results are currently available [161-163]. In particular creatine supplementation associated with resistance training or exhaustive exercise training has been associated either with reduced oxidative stress [162, 164], increased free radical generation and related consumption of antioxidant reserves [161] or no change of lipid peroxidation, resistance of low density lipoprotein to oxidative stress or plasma concentrations of non-enzymatic antioxidants [163]. Taken together these observations show that creatine supplementation before strenuous endurance exercise reduces the increase of markers of cell death/lysis and muscle soreness suggesting a positive effect of the supplementation strategy in maintaining muscle integrity after intense prolonged exercise. The mechanisms underlying such a protective effect are only partially known.

6. Essential amino acids

Considering that mechanical stimuli may induce skeletal muscle damage as a consequence of overload and/or eccentric actions causing cytoskeleton and subcellular disruption on muscle fibers, it appears that nutritional interventions finalized to maximize protein synthesis (MPS) or minimize protein catabolism (MPC) would be helpful in preventing and/or treating exercise induced muscle injuries.

As known MPS includes the complex process of mRNA translation which develops in three consecutive steps i.e. initiation, in which the initiator methionyl-tRNA and mRNA bind to 40S ribosomal subunit, elongation, by which tRNA-bound amino acids are incorporated into growing polypeptide chains according to the mRNA template, and termination, where the completed protein is released from the ribosome [165].

The first two steps of mRNA translation are highly regulated at two different levels: the binding of methionyl-tRNA to 40S ribosomal subunit to form 43S preinitiation complex, and recognition, unwinding, and binding of mRNA to the 43S, catalyzed by a multi-subunit complex of eukaryotic factors (eIFs), referred to as eIF4F. The mammalian target of rapamycin (mTOR) kinase which is now recognized as a key regulator of cell growth and a pivotal sensor of nutritional status, is a key regulator of MPS. In cells, mTOR forms two distinct complexes, mTORC1 and mTORC2, depending on the binding partners. When bound to raptor (regulatory associated protein of mTOR) mTOR forms mTORC1, which mediates the effects sensitive to rapamycin [166]. mTOR-mediated regulates protein synthesis is based on Activation of elF4E binding protein-1 (4E-BP1) releases the inhibition on the eukaryotic factors complex eIF4F, which is responsible for the interaction with 40s ribosomal subunit and translation initiation [167]. In fact when 4E-BP1 is in its hypophosphorylated state it blocks the ability of eIF4E to bind to eIF4G and forms an inactive 4E-BP1-eIF4E complex. This interaction precludes mRNA to bind to the ribosome. mTORC1 is also responsible for the activation of downstream S6K1. S6K1 is a kinase which requires phosphorylation at two sites and its activation is necessary for muscle fibres to achieve normal size, since S6K1 knockout cells are smaller than control cells [168]. Following phosphorylation at Thr389 by mTORC1, S6K1 regulates the activity of eukaryotic elongation factor 2 kinase (eEF2k) [169].

Studies in animals models and humans showed that essential amino acids (EAA) [170, 171] unlike non EAA [170], are fundamental regulators of MPS and mitochondrial biogenesis [172]. It has been shown that hyperaminoacidemia stimulates amino acid transport and net MPS, unlike carbohydrate administration both in the young [173] and in the elderly [174]. The effects on protein synthesis arise independently of changes in anabolic hormone concentration [175, 176], although insulin is required for the effects of EAA on translation [177]. Among EAA, Branched chain amino acids (BCAA: leucine, isoleucine and valine) play a very important role as nutrient signals that regulates MPS through the stimulation of insulin-independent and rapamycin-sensitive pathways [178, 179]. In particular available data suggest that at least part of the postprandial translational activation is to be attributed to BCAAs through activation of mTOR and downstream signals (elF4G, S6K1 and 4E-BP1). Although mTOR is the key integrator of the anabolic response to BCAA, mTOR itself may not be the direct target of EAA. It has been shown that inhibition by the upstream TSC1/2 complex represents the mechanism through which leucine and insulin upregulate mTOR and downstream targets.

The scenario arising from available studies indicates that the physiological anabolic response to BCAA may help counteracting the metabolic unbalance induced by exercise and in particular resistance training which has been linked to concurrent increase of MPS and MPC [180, 181] and negative changes in circulating free amino acids [182]. In these conditions the exercise-triggered hypercatabolism may be counteracted by amino acids supplementation which in turn has been related with net protein synthesis when combined with bouts of resistance exercise [173, 183, 184] and prevented BCAA exercise-induced oxidation [182].

Recent studies suggest that BCAA supplementation, by promoting MPS, may improve the repair of muscle damage induced by resistance exercise.

In particular Nosaka et al. [185] showed that an amino acid supplement containing around 60% BCAA was effective in reducing muscle damage and soreness when consumed immediately before (30 min) and during the four days of recovery following a damaging bout of lengthening contractions of the elbow flexors. Later Jackman and coworkers reported the effects of BCAA supplementation during recovery from intense eccentric exercise consisting in 12 x 10 repetitions of unilateral eccentric knee extension in male untrained subjects. A decrease in flexed muscle soreness was observed in supplemented compared with placebo group at 48 h and 72 h post exercise whereas the degree of force loss and the fluctuation of blood markers of muscle damage appeared unchanged between groups [186]. Similar results were obtained in female untrained young subjects by Shimomura et al. [187] examining the effects of BCAA supplementation on squat-exercise-induced DOMS. In this report the participants ingested either BCAA (isoleucine:leucine:valine = 1:2.3:1.2) or dextrin at 100 mg/kg body weight just before the squat exercise consisting of 7 sets of 20 squats/set with 3-min intervals between sets. The peak of DOMS was reached two or three days post exercise but the level of soreness was significantly lower in the BCAA trial than in the placebo. Interestingly three day post exercise the force decrease observed in the placebo appeared to be prevented by BCAA supplementation. Accordingly plasma myoglobin and elastase (index of neutrophil activation) appeared to be increased by exercise in the placebo but not in the BCAA group [187].

Interestingly the beneficial effects of BCAA mixtures supplementation has been reported also following moderate resistance training and endurance training both in rodents [188] and humans [189-191]. In these conditions the effect of supplementation seems to mainly reflected on a reduced rate of perceived exertion (RPE) [189] and reduced proteolysis as demonstrated by reduced phenyalanine release from the muscle [192], whereas no beneficial effects have been found in terms of changes in exercise performance [189]. In particular in the study by Greer and coworkers nine untrained male subjects where supplemented with a BCAA enriched beverage, an isocaloric, carbohydrate (CHO) beverage or a noncaloric placebo beverage. The subjects performed three 90-minute cycling bouts at 55% VO2 peak followed by 15-minute time trials and ingested a total of 200 kcal via the CHO or BCAA beverage before and at 60 minutes of exercise or the placebo beverage on the same time course. A greater distance was traveled during the CHO trial than the BCAA and placebo trial. On the contrary the RPE was reduced during the BCAA trial as compared with the placebo trial. This study clearly demonstrated that CHO supplementation improved performance compared with BCAA and PLAC beverage. Thus BCAA supplementation did not influence aerobic performance but attenuated RPE [189]. Accordingly BCAA supplementation (0.8% BCAA in a 3.5% carbohydrate solution; 2,500 mL/day for four days) effectively reduced the muscle soreness and fatigue sensation when supplementation was carried out during an intensive endurance training programme in male and female, and the perceived changes could be attributed to the attenuation of muscle damage as demonstrated by decreased LDH, CK and granulocyte elastase levels, and inflammation [190, 191].

Importantly a minority of works contradict the general findings from other research on the benefits of BCAA on resistance exercise muscle damage. In particular conflicting results have been reported by Stock et al. [193] showing that in a mixed sex group of trained participants there were no differences in damage indices of resistance exercise (6 sets of squats to fatigue using 75% of the 1 repetition maximum) between a carbohydrate versus a carbohydrate/leucine supplement. The subjects enrolled consumed the carbohydrate beverage 30 minutes before and immediately after exercise with or without the addition of 22.5 mg kg-1 of leucine. Results showed that the addition of leucine did not significantly decrease CK and LDH activity or DOMS evaluated at different time points following exercise thus suggesting that adding leucine to carbohydrate beverages did not affect acute muscle recovery from exercise. Considering that in the study by Stock and coworkers the amino acid supplement consisted of leucine alone (and not of a mixture of BCAA), one can speculate that a methodological bias may account for the observed different outcome of this study compared to others.

In conclusion the overall effect of resistance exercise on circulating BCAA suggests that exercise induced muscle damage is followed by an increase of skeletal muscle BCAA uptake from the serum being used as energy source and/or participate in translation initiation signaling pathway involved in muscle remodeling. Functionally this appears to have some consequence in muscle pain. A similar effect on the rate of perceived exertion has been found following BCAA supplementation before and during endurance exercise, when muscle remodeling is reasonably much less than in resistance exercise. The mechanisms beyond the protective effects of BCAA supplementation on muscle damage deserve further investigations, to be mostly oriented on unraveling the effects of supplements on inflammation.

7. Conclusions

The skeletal muscle is placed under considerable stress during high repetitive eccentric, or lengthening, contractions.

Several studies have used a variety of nutritional supplementation strategies including macronutrients and micronutrients, with variations in dosage, timing and duration of supplementation, finalized to minimize exercise induced muscle injury. Although there is proper rationale and some evidence showing the efficacy of certain supplements such as creatine and essential amino acids, there is little evidence to support a role for others including the antioxidants. Indeed, antioxidant supplementation may interfere with the cellular signalling paths thereby unfavorably affecting muscle function, performance, and recovery from injury.


1 - Hough T. Ergographic Studies in Muscular Fatigue and Soreness. Journal. 1900 Nov 20;5(3):81-92.
2 - McHugh MP. Recent advances in the understanding of the repeated bout effect: the protective effect against muscle damage from a single bout of eccentric exercise. Scandinavian journal of medicine & science in sports. 2003 Apr;13(2):88-97.
3 - Ciciliot S, Schiaffino S. Regeneration of mammalian skeletal muscle. Basic mechanisms and clinical implications. Current pharmaceutical design. 2010;16(8):906-14.
4 - Allen DG. Eccentric muscle damage: mechanisms of early reduction of force. Acta physiologica Scandinavica. 2001 Mar;171(3):311-9.
5 - Armstrong RB. Initial events in exercise-induced muscular injury. Medicine and science in sports and exercise. 1990 Aug;22(4):429-35.
6 - Clarkson PM, Hubal MJ. Exercise-induced muscle damage in humans. American journal of physical medicine & rehabilitation / Association of Academic Physiatrists. 2002 Nov;81(11 Suppl):S52-69.
7 - Ebbeling CB, Clarkson PM. Exercise-induced muscle damage and adaptation. Sports medicine (Auckland, NZ. 1989 Apr;7(4):207-34.
8 - Lieber RL, Friden J. Selective damage of fast glycolytic muscle fibres with eccentric contraction of the rabbit tibialis anterior. Acta physiologica Scandinavica. 1988 Aug;133(4):587-8.
9 - Lieber RL, Thornell LE, Friden J. Muscle cytoskeletal disruption occurs within the first 15 min of cyclic eccentric contraction. J Appl Physiol. 1996 Jan;80(1):278-84.
10 - Armstrong RB, Ogilvie RW, Schwane JA. Eccentric exercise-induced injury to rat skeletal muscle. J Appl Physiol. 1983 Jan;54(1):80-93.
11 - Friden J, Seger J, Sjostrom M, Ekblom B. Adaptive response in human skeletal muscle subjected to prolonged eccentric training. International journal of sports medicine. 1983 Aug;4(3):177-83.
12 - Friden J, Sjostrom M, Ekblom B. Myofibrillar damage following intense eccentric exercise in man. International journal of sports medicine. 1983 Aug;4(3):170-6.
13 - Newham DJ, McPhail G, Mills KR, Edwards RH. Ultrastructural changes after concentric and eccentric contractions of human muscle. Journal of the neurological sciences. 1983 Sep;61(1):109-22.
14 - Ogilvie RW, Armstrong RB, Baird KE, Bottoms CL. Lesions in the rat soleus muscle following eccentrically biased exercise. The American journal of anatomy. 1988 Aug;182(4):335-46.
15 - Armstrong RB, Warren GL, Warren JA. Mechanisms of exercise-induced muscle fibre injury. Sports medicine (Auckland, NZ. 1991 Sep;12(3):184-207.
16 - Takekura H, Fujinami N, Nishizawa T, Ogasawara H, Kasuga N. Eccentric exercise-induced morphological changes in the membrane systems involved in excitation-contraction coupling in rat skeletal muscle. The Journal of physiology. 2001 Jun 1;533(Pt 2):571-83.
17 - Pedersen BK. Special feature for the Olympics: effects of exercise on the immune system: exercise and cytokines. Immunology and cell biology. 2000 Oct;78(5):532-5.
18 - Ostrowski K, Hermann C, Bangash A, Schjerling P, Nielsen JN, Pedersen BK. A trauma-like elevation of plasma cytokines in humans in response to treadmill running. The Journal of physiology. 1998 Dec 15;513 ( Pt 3):889-94.
19 - Filep JG, Beauchamp M, Baron C, Paquette Y. Peroxynitrite mediates IL-8 gene expression and production in lipopolysaccharide-stimulated human whole blood. J Immunol. 1998 Nov 15;161(10):5656-62.
20 - Li JJ, Oberley LW. Overexpression of manganese-containing superoxide dismutase confers resistance to the cytotoxicity of tumor necrosis factor alpha and/or hyperthermia. Cancer research. 1997 May 15;57(10):1991-8.
21 - Hikida RS, Staron RS, Hagerman FC, Sherman WM, Costill DL. Muscle fiber necrosis associated with human marathon runners. Journal of the neurological sciences. 1983 May;59(2):185-203.
22 - Packer L, Cadenas E. Oxidants and antioxidants revisited. New concepts of oxidative stress. Free radical research. 2007 Sep;41(9):951-2.
23 - McCord JM. The superoxide free radical: its biochemistry and pathophysiology. Surgery. 1983 Sep;94(3):412-4.
24 - Jackson MJ, Pye D, Palomero J. The production of reactive oxygen and nitrogen species by skeletal muscle. J Appl Physiol. 2007 Apr;102(4):1664-70.
25 - Jackson MJ, O'Farrell S. Free radicals and muscle damage. British medical bulletin. 1993 Jul;49(3):630-41.
26 - McGinley C, Shafat A, Donnelly AE. Does antioxidant vitamin supplementation protect against muscle damage? Sports medicine (Auckland, NZ. 2009;39(12):1011-32.
27 - Bloomer RJ, Goldfarb AH. Anaerobic exercise and oxidative stress: a review. Canadian journal of applied physiology = Revue canadienne de physiologie appliquee. 2004 Jun;29(3):245-63.
28 - McArdle A, Vasilaki A, Jackson M. Exercise and skeletal muscle ageing: cellular and molecular mechanisms. Ageing research reviews. 2002 Feb;1(1):79-93.
29 - Peternelj TT, Coombes JS. Antioxidant supplementation during exercise training: beneficial or detrimental? Sports medicine (Auckland, NZ. 2010 Dec 1;41(12):1043-69.
30 - Jakeman P, Maxwell S. Effect of antioxidant vitamin supplementation on muscle function after eccentric exercise. European journal of applied physiology and occupational physiology. 1993;67(5):426-30.
31 - Palazzetti S, Rousseau AS, Richard MJ, Favier A, Margaritis I. Antioxidant supplementation preserves antioxidant response in physical training and low antioxidant intake. The British journal of nutrition. 2004 Jan;91(1):91-100.
32 - Nakhostin-Roohi B, Babaei P, Rahmani-Nia F, Bohlooli S. Effect of vitamin C supplementation on lipid peroxidation, muscle damage and inflammation after 30-min exercise at 75% VO2max. The Journal of sports medicine and physical fitness. 2008 Jun;48(2):217-24.
33 - Bloomer RJ, Goldfarb AH, McKenzie MJ, You T, Nguyen L. Effects of antioxidant therapy in women exposed to eccentric exercise. International journal of sport nutrition and exercise metabolism. 2004 Aug;14(4):377-88.
34 - Bryer SC, Goldfarb AH. Effect of high dose vitamin C supplementation on muscle soreness, damage, function, and oxidative stress to eccentric exercise. International journal of sport nutrition and exercise metabolism. 2006 Jun;16(3):270-80.
35 - Nieman DC, Peters EM, Henson DA, Nevines EI, Thompson MM. Influence of vitamin C supplementation on cytokine changes following an ultramarathon. J Interferon Cytokine Res. 2000 Nov;20(11):1029-35.
36 - Phillips T, Childs AC, Dreon DM, Phinney S, Leeuwenburgh C. A dietary supplement attenuates IL-6 and CRP after eccentric exercise in untrained males. Medicine and science in sports and exercise. 2003 Dec;35(12):2032-7.
37 - Funes L, Carrera-Quintanar L, Cerdan-Calero M, Ferrer MD, Drobnic F, Pons A, et al. Effect of lemon verbena supplementation on muscular damage markers, proinflammatory cytokines release and neutrophils' oxidative stress in chronic exercise. European journal of applied physiology. 2011 Apr;111(4):695-705.
38 - Peters EM, Anderson R, Nieman DC, Fickl H, Jogessar V. Vitamin C supplementation attenuates the increases in circulating cortisol, adrenaline and anti-inflammatory polypeptides following ultramarathon running. International journal of sports medicine. 2001 Oct;22(7):537-43.
39 - Senturk UK, Yalcin O, Gunduz F, Kuru O, Meiselman HJ, Baskurt OK. Effect of antioxidant vitamin treatment on the time course of hematological and hemorheological alterations after an exhausting exercise episode in human subjects. J Appl Physiol. 2005 Apr;98(4):1272-9.
40 - Nakazato K, Ochi E, Waga T. Dietary apple polyphenols have preventive effects against lengthening contraction-induced muscle injuries. Molecular nutrition & food research. 2010 Mar;54(3):364-72.
41 - Bowtell JL, Sumners DP, Dyer A, Fox P, Mileva KN. Montmorency cherry juice reduces muscle damage caused by intensive strength exercise. Medicine and science in sports and exercise. 2011 Aug;43(8):1544-51.
42 - Matsumoto H, Takenami E, Iwasaki-Kurashige K, Osada T, Katsumura T, Hamaoka T. Effects of blackcurrant anthocyanin intake on peripheral muscle circulation during typing work in humans. European journal of applied physiology. 2005 May;94(1-2):36-45.
43 - Reid MB, Stokic DS, Koch SM, Khawli FA, Leis AA. N-acetylcysteine inhibits muscle fatigue in humans. The Journal of clinical investigation. 1994 Dec;94(6):2468-74.
44 - Kanter M. Free radicals and exercise: effects of nutritional antioxidant supplementation. Exercise and sport sciences reviews. 1995;23:375-97.
45 - Beaton LJ, Allan DA, Tarnopolsky MA, Tiidus PM, Phillips SM. Contraction-induced muscle damage is unaffected by vitamin E supplementation. Medicine and science in sports and exercise. 2002 May;34(5):798-805.
46 - Thompson D, Bailey DM, Hill J, Hurst T, Powell JR, Williams C. Prolonged vitamin C supplementation and recovery from eccentric exercise. European journal of applied physiology. 2004 Jun;92(1-2):133-8.
47 - Silva LA, Pinho CA, Silveira PC, Tuon T, De Souza CT, Dal-Pizzol F, et al. Vitamin E supplementation decreases muscular and oxidative damage but not inflammatory response induced by eccentric contraction. J Physiol Sci. 2010 Jan;60(1):51-7.
48 - Mastaloudis A, Morrow JD, Hopkins DW, Devaraj S, Traber MG. Antioxidant supplementation prevents exercise-induced lipid peroxidation, but not inflammation, in ultramarathon runners. Free radical biology & medicine. 2004 May 15;36(10):1329-41.
49 - Nieman DC, Henson DA, Gross SJ, Jenkins DP, Davis JM, Murphy EA, et al. Quercetin reduces illness but not immune perturbations after intensive exercise. Medicine and science in sports and exercise. 2007 Sep;39(9):1561-9.
50 - Kaikkonen J, Kosonen L, Nyyssonen K, Porkkala-Sarataho E, Salonen R, Korpela H, et al. Effect of combined coenzyme Q10 and d-alpha-tocopheryl acetate supplementation on exercise-induced lipid peroxidation and muscular damage: a placebo-controlled double-blind study in marathon runners. Free radical research. 1998 Jul;29(1):85-92.
51 - Dawson B, Henry GJ, Goodman C, Gillam I, Beilby JR, Ching S, et al. Effect of Vitamin C and E supplementation on biochemical and ultrastructural indices of muscle damage after a 21 km run. International journal of sports medicine. 2002 Jan;23(1):10-5.
52 - Thompson D, Williams C, Kingsley M, Nicholas CW, Lakomy HK, McArdle F, et al. Muscle soreness and damage parameters after prolonged intermittent shuttle-running following acute vitamin C supplementation. International journal of sports medicine. 2001 Jan;22(1):68-75.
53 - Jowko E, Sacharuk J, Balasinska B, Wilczak J, Charmas M, Ostaszewski P, et al. Effect of a single dose of green tea polyphenols on the blood markers of exercise-induced oxidative stress in soccer players. International journal of sport nutrition and exercise metabolism. 2012 Dec;22(6):486-96.
54 - Connolly DA, Lauzon C, Agnew J, Dunn M, Reed B. The effects of vitamin C supplementation on symptoms of delayed onset muscle soreness. The Journal of sports medicine and physical fitness. 2006 Sep;46(3):462-7.
55 - Close GL, Ashton T, Cable T, Doran D, Holloway C, McArdle F, et al. Ascorbic acid supplementation does not attenuate post-exercise muscle soreness following muscle-damaging exercise but may delay the recovery process. The British journal of nutrition. 2006 May;95(5):976-81.
56 - Thompson D, Williams C, Garcia-Roves P, McGregor SJ, McArdle F, Jackson MJ. Post-exercise vitamin C supplementation and recovery from demanding exercise. European journal of applied physiology. 2003 May;89(3-4):393-400.
57 - Ganio MS, Armstrong LE, Johnson EC, Klau JF, Ballard KD, Michniak-Kohn B, et al. Effect of quercetin supplementation on maximal oxygen uptake in men and women. Journal of sports sciences. 2010 Jan;28(2):201-8.
58 - Gomez-Cabrera MC, Domenech E, Vina J. Moderate exercise is an antioxidant: upregulation of antioxidant genes by training. Free radical biology & medicine. 2008 Jan 15;44(2):126-31.
59 - McArdle F, Spiers S, Aldemir H, Vasilaki A, Beaver A, Iwanejko L, et al. Preconditioning of skeletal muscle against contraction-induced damage: the role of adaptations to oxidants in mice. The Journal of physiology. 2004 Nov 15;561(Pt 1):233-44.
60 - Tiidus PM, Pushkarenko J, Houston ME. Lack of antioxidant adaptation to short-term aerobic training in human muscle. The American journal of physiology. 1996 Oct;271(4 Pt 2):R832-6.
61 - Margaritis I, Tessier F, Richard MJ, Marconnet P. No evidence of oxidative stress after a triathlon race in highly trained competitors. International journal of sports medicine. 1997 Apr;18(3):186-90.
62 - Teixeira VH, Valente HF, Casal SI, Marques AF, Moreira PA. Antioxidants do not prevent postexercise peroxidation and may delay muscle recovery. Medicine and science in sports and exercise. 2009 Sep;41(9):1752-60.
63 - Childs A, Jacobs C, Kaminski T, Halliwell B, Leeuwenburgh C. Supplementation with vitamin C and N-acetyl-cysteine increases oxidative stress in humans after an acute muscle injury induced by eccentric exercise. Free radical biology & medicine. 2001 Sep 15;31(6):745-53.
64 - Avery NG, Kaiser JL, Sharman MJ, Scheett TP, Barnes DM, Gomez AL, et al. Effects of vitamin E supplementation on recovery from repeated bouts of resistance exercise. Journal of strength and conditioning research / National Strength & Conditioning Association. 2003 Nov;17(4):801-9.
65 - Malm C, Svensson M, Sjoberg B, Ekblom B, Sjodin B. Supplementation with ubiquinone-10 causes cellular damage during intense exercise. Acta physiologica Scandinavica. 1996 Aug;157(4):511-2.
66 - Malm C, Svensson M, Ekblom B, Sjodin B. Effects of ubiquinone-10 supplementation and high intensity training on physical performance in humans. Acta physiologica Scandinavica. 1997 Nov;161(3):379-84.
67 - Lamprecht M, Hofmann P, Greilberger JF, Schwaberger G. Increased lipid peroxidation in trained men after 2 weeks of antioxidant supplementation. International journal of sport nutrition and exercise metabolism. 2009 Aug;19(4):385-99.
68 - Nieman DC, Henson DA, McAnulty SR, McAnulty LS, Morrow JD, Ahmed A, et al. Vitamin E and immunity after the Kona Triathlon World Championship. Medicine and science in sports and exercise. 2004 Aug;36(8):1328-35.
69 - Knez WL, Jenkins DG, Coombes JS. Oxidative stress in half and full Ironman triathletes. Medicine and science in sports and exercise. 2007 Feb;39(2):283-8.
70 - Thompson D, Williams C, McGregor SJ, Nicholas CW, McArdle F, Jackson MJ, et al. Prolonged vitamin C supplementation and recovery from demanding exercise. International journal of sport nutrition and exercise metabolism. 2001 Dec;11(4):466-81.
71 - Khassaf M, McArdle A, Esanu C, Vasilaki A, McArdle F, Griffiths RD, et al. Effect of vitamin C supplements on antioxidant defence and stress proteins in human lymphocytes and skeletal muscle. The Journal of physiology. 2003 Jun 1;549(Pt 2):645-52.
72 - Ashton T, Rowlands CC, Jones E, Young IS, Jackson SK, Davies B, et al. Electron spin resonance spectroscopic detection of oxygen-centred radicals in human serum following exhaustive exercise. European journal of applied physiology and occupational physiology. 1998 May;77(6):498-502.
73 - Kaminski M, Boal R. An effect of ascorbic acid on delayed-onset muscle soreness. Pain. 1992 Sep;50(3):317-21.
74 - Packer L. Oxidants, antioxidant nutrients and the athlete. Journal of sports sciences. 1997 Jun;15(3):353-63.
75 - Bowry VW, Mohr D, Cleary J, Stocker R. Prevention of tocopherol-mediated peroxidation in ubiquinol-10-free human low density lipoprotein. The Journal of biological chemistry. 1995 Mar 17;270(11):5756-63.
76 - Cannon JG, Orencole SF, Fielding RA, Meydani M, Meydani SN, Fiatarone MA, et al. Acute phase response in exercise: interaction of age and vitamin E on neutrophils and muscle enzyme release. The American journal of physiology. 1990 Dec;259(6 Pt 2):R1214-9.
77 - McBride JM, Kraemer WJ, Triplett-McBride T, Sebastianelli W. Effect of resistance exercise on free radical production. Medicine and science in sports and exercise. 1998 Jan;30(1):67-72.
78 - Rebouche CJ. Synthesis of carnitine precursors and related compounds. Methods in enzymology. 1986;123:290-7.
79 - Rebouche CJ, Paulson DJ. Carnitine metabolism and function in humans. Annual review of nutrition. 1986;6:41-66.
80 - Weis BC, Cowan AT, Brown N, Foster DW, McGarry JD. Use of a selective inhibitor of liver carnitine palmitoyltransferase I (CPT I) allows quantification of its contribution to total CPT I activity in rat heart. Evidence that the dominant cardiac CPT I isoform is identical to the skeletal muscle enzyme. The Journal of biological chemistry. 1994 Oct 21;269(42):26443-8.
81 - Vaz FM, Wanders RJ. Carnitine biosynthesis in mammals. The Biochemical journal. 2002 Feb 1;361(Pt 3):417-29.
82 - Brass EP. Supplemental carnitine and exercise. The American journal of clinical nutrition. 2000 Aug;72(2 Suppl):618S-23S.
83 - Bremer J. Carnitine--metabolism and functions. Physiological reviews. 1983 Oct;63(4):1420-80.
84 - Rebouche CJ, Bosch EP, Chenard CA, Schabold KJ, Nelson SE. Utilization of dietary precursors for carnitine synthesis in human adults. The Journal of nutrition. 1989 Dec;119(12):1907-13.
85 - Kendler BS. Carnitine: an overview of its role in preventive medicine. Preventive medicine. 1986 Jul;15(4):373-90.
86 - Brass EP. Pharmacokinetic considerations for the therapeutic use of carnitine in hemodialysis patients. Clinical therapeutics. 1995 Mar-Apr;17(2):176-85; discussion 5.
87 - Proulx F, Lacroix J, Qureshi IA, Nadeau D, Gauthier M, Lambert M. Acquired carnitine abnormalities in critically ill children. European journal of pediatrics. 1997 Nov;156(11):864-9.
88 - Karlic H, Lohninger A. Supplementation of L-carnitine in athletes: does it make sense? Nutrition (Burbank, Los Angeles County, Calif. 2004 Jul-Aug;20(7-8):709-15.
89 - Arenas J, Huertas R, Campos Y, Diaz AE, Villalon JM, Vilas E. Effects of L-carnitine on the pyruvate dehydrogenase complex and carnitine palmitoyl transferase activities in muscle of endurance athletes. FEBS letters. 1994 Mar 14;341(1):91-3.
90 - Huertas R, Campos Y, Diaz E, Esteban J, Vechietti L, Montanari G, et al. Respiratory chain enzymes in muscle of endurance athletes: effect of L-carnitine. Biochemical and biophysical research communications. 1992 Oct 15;188(1):102-7.
91 - Brass EP, Hiatt WR. The role of carnitine and carnitine supplementation during exercise in man and in individuals with special needs. Journal of the American College of Nutrition. 1998 Jun;17(3):207-15.
92 - Dragan IG, Vasiliu A, Georgescu E, Eremia N. Studies concerning chronic and acute effects of L-carnitina in elite athletes. Physiologie. 1989 Apr-Jun;26(2):111-29.
93 - Dragan GI, Wagner W, Ploesteanu E. Studies concerning the ergogenic value of protein supply and 1-carnitine in elite junior cyclists. Physiologie. 1988 Jul-Sep;25(3):129-32.
94 - Vecchiet L, Di Lisa F, Pieralisi G, Ripari P, Menabo R, Giamberardino MA, et al. Influence of L-carnitine administration on maximal physical exercise. European journal of applied physiology and occupational physiology. 1990;61(5-6):486-90.
95 - Arenas J, Ricoy JR, Encinas AR, Pola P, D'Iddio S, Zeviani M, et al. Carnitine in muscle, serum, and urine of nonprofessional athletes: effects of physical exercise, training, and L-carnitine administration. Muscle & nerve. 1991 Jul;14(7):598-604.
96 - Barnett C, Costill DL, Vukovich MD, Cole KJ, Goodpaster BH, Trappe SW, et al. Effect of L-carnitine supplementation on muscle and blood carnitine content and lactate accumulation during high-intensity sprint cycling. International journal of sport nutrition. 1994 Sep;4(3):280-8.
97 - Vukovich MD, Costill DL, Fink WJ. Carnitine supplementation: effect on muscle carnitine and glycogen content during exercise. Medicine and science in sports and exercise. 1994 Sep;26(9):1122-9.
98 - Colombani P, Wenk C, Kunz I, Krahenbuhl S, Kuhnt M, Arnold M, et al. Effects of L-carnitine supplementation on physical performance and energy metabolism of endurance-trained athletes: a double-blind crossover field study. European journal of applied physiology and occupational physiology. 1996;73(5):434-9.
99 - Nuesch R, Rossetto M, Martina B. Plasma and urine carnitine concentrations in well-trained athletes at rest and after exercise. Influence of L-carnitine intake. Drugs under experimental and clinical research. 1999;25(4):167-71.
100 - Trappe SW, Costill DL, Goodpaster B, Vukovich MD, Fink WJ. The effects of L-carnitine supplementation on performance during interval swimming. International journal of sports medicine. 1994 May;15(4):181-5.
101 - Oyono-Enguelle S, Freund H, Ott C, Gartner M, Heitz A, Marbach J, et al. Prolonged submaximal exercise and L-carnitine in humans. European journal of applied physiology and occupational physiology. 1988;58(1-2):53-61.
102 - Giamberardino MA, Dragani L, Valente R, Di Lisa F, Saggini R, Vecchiet L. Effects of prolonged L-carnitine administration on delayed muscle pain and CK release after eccentric effort. International journal of sports medicine. 1996 Jul;17(5):320-4.
103 - Volek JS, Kraemer WJ, Rubin MR, Gomez AL, Ratamess NA, Gaynor P. L-Carnitine L-tartrate supplementation favorably affects markers of recovery from exercise stress. American journal of physiology. 2002 Feb;282(2):E474-82.
104 - Kraemer WJ, Volek JS, French DN, Rubin MR, Sharman MJ, Gomez AL, et al. The effects of L-carnitine L-tartrate supplementation on hormonal responses to resistance exercise and recovery. Journal of strength and conditioning research / National Strength & Conditioning Association. 2003 Aug;17(3):455-62.
105 - Spiering BA, Kraemer WJ, Vingren JL, Hatfield DL, Fragala MS, Ho JY, et al. Responses of criterion variables to different supplemental doses of L-carnitine L-tartrate. Journal of strength and conditioning research / National Strength & Conditioning Association. 2007 Feb;21(1):259-64.
106 - Ho JY, Kraemer WJ, Volek JS, Fragala MS, Thomas GA, Dunn-Lewis C, et al. l-Carnitine l-tartrate supplementation favorably affects biochemical markers of recovery from physical exertion in middle-aged men and women. Metabolism: clinical and experimental. 2010 Aug;59(8):1190-9.
107 - Reid MB, Haack KE, Franchek KM, Valberg PA, Kobzik L, West MS. Reactive oxygen in skeletal muscle. I. Intracellular oxidant kinetics and fatigue in vitro. J Appl Physiol. 1992 Nov;73(5):1797-804.
108 - Westerblad H, Allen DG. Cellular mechanisms of skeletal muscle fatigue. Advances in experimental medicine and biology. 2003;538:563-70; discussion 71.
109 - Bruton JD, Place N, Yamada T, Silva JP, Andrade FH, Dahlstedt AJ, et al. Reactive oxygen species and fatigue-induced prolonged low-frequency force depression in skeletal muscle fibres of rats, mice and SOD2 overexpressing mice. The Journal of physiology. 2008 Jan 1;586(1):175-84.
110 - Brass EP, Scarrow AM, Ruff LJ, Masterson KA, Van Lunteren E. Carnitine delays rat skeletal muscle fatigue in vitro. J Appl Physiol. 1993 Oct;75(4):1595-600.
111 - Gulcin I. Antioxidant and antiradical activities of L-carnitine. Life sciences. 2006 Jan 18;78(8):803-11.
112 - Vina J, Gimeno A, Sastre J, Desco C, Asensi M, Pallardo FV, et al. Mechanism of free radical production in exhaustive exercise in humans and rats; role of xanthine oxidase and protection by allopurinol. IUBMB life. 2000 Jun;49(6):539-44.
113 - Duarte JA, Appell HJ, Carvalho F, Bastos ML, Soares JM. Endothelium-derived oxidative stress may contribute to exercise-induced muscle damage. International journal of sports medicine. 1993 Nov;14(8):440-3.
114 - Heunks LM, Vina J, van Herwaarden CL, Folgering HT, Gimeno A, Dekhuijzen PN. Xanthine oxidase is involved in exercise-induced oxidative stress in chronic obstructive pulmonary disease. The American journal of physiology. 1999 Dec;277(6 Pt 2):R1697-704.
115 - Casas H, Murtra B, Casas M, Ibanez J, Ventura JL, Ricart A, et al. Increased blood ammonia in hypoxia during exercise in humans. Journal of physiology and biochemistry. 2001 Dec;57(4):303-12.
116 - Parolin ML, Spriet LL, Hultman E, Hollidge-Horvat MG, Jones NL, Heigenhauser GJ. Regulation of glycogen phosphorylase and PDH during exercise in human skeletal muscle during hypoxia. American journal of physiology. 2000 Mar;278(3):E522-34.
117 - Greenwood M, Farris J, Kreider R, Greenwood L, Byars A. Creatine supplementation patterns and perceived effects in select division I collegiate athletes. Clin J Sport Med. 2000 Jul;10(3):191-4.
118 - LaBotz M, Smith BW. Creatine supplement use in an NCAA Division I athletic program. Clin J Sport Med. 1999 Jul;9(3):167-9.
119 - McGuine TA, Sullivan JC, Bernhardt DA. Creatine supplementation in Wisconsin high school athletes. Wmj. 2002;101(2):25-30.
120 - McGuine TA, Sullivan JC, Bernhardt DT. Creatine supplementation in high school football players. Clin J Sport Med. 2001 Oct;11(4):247-53.
121 - Juhn MS, O'Kane JW, Vinci DM. Oral creatine supplementation in male collegiate athletes: a survey of dosing habits and side effects. Journal of the American Dietetic Association. 1999 May;99(5):593-5.
122 - Ronsen O, Sundgot-Borgen J, Maehlum S. Supplement use and nutritional habits in Norwegian elite athletes. Scandinavian journal of medicine & science in sports. 1999 Feb;9(1):28-35.
123 - Volek JS, Duncan ND, Mazzetti SA, Staron RS, Putukian M, Gomez AL, et al. Performance and muscle fiber adaptations to creatine supplementation and heavy resistance training. Medicine and science in sports and exercise. 1999 Aug;31(8):1147-56.
124 - Tarnopolsky MA. Potential benefits of creatine monohydrate supplementation in the elderly. Current opinion in clinical nutrition and metabolic care. 2000 Nov;3(6):497-502.
125 - Tarnopolsky MA, MacLennan DP. Creatine monohydrate supplementation enhances high-intensity exercise performance in males and females. International journal of sport nutrition and exercise metabolism. 2000 Dec;10(4):452-63.
126 - Harris RC, Soderlund K, Hultman E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci (Lond). 1992 Sep;83(3):367-74.
127 - van Loon LJ, Oosterlaar AM, Hartgens F, Hesselink MK, Snow RJ, Wagenmakers AJ. Effects of creatine loading and prolonged creatine supplementation on body composition, fuel selection, sprint and endurance performance in humans. Clin Sci (Lond). 2003 Feb;104(2):153-62.
128 - Van Schuylenbergh R, Van Leemputte M, Hespel P. Effects of oral creatine-pyruvate supplementation in cycling performance. International journal of sports medicine. 2003 Feb;24(2):144-50.
129 - Izquierdo M, Ibanez J, Gonzalez-Badillo JJ, Gorostiaga EM. Effects of creatine supplementation on muscle power, endurance, and sprint performance. Medicine and science in sports and exercise. 2002 Feb;34(2):332-43.
130 - Willoughby DS, Rosene J. Effects of oral creatine and resistance training on myosin heavy chain expression. Medicine and science in sports and exercise. 2001 Oct;33(10):1674-81.
131 - Willoughby DS, Rosene JM. Effects of oral creatine and resistance training on myogenic regulatory factor expression. Medicine and science in sports and exercise. 2003 Jun;35(6):923-9.
132 - Hespel P, Op't Eijnde B, Van Leemputte M, Urso B, Greenhaff PL, Labarque V, et al. Oral creatine supplementation facilitates the rehabilitation of disuse atrophy and alters the expression of muscle myogenic factors in humans. The Journal of physiology. 2001 Oct 15;536(Pt 2):625-33.
133 - Bemben MG, Bemben DA, Loftiss DD, Knehans AW. Creatine supplementation during resistance training in college football athletes. Medicine and science in sports and exercise. 2001 Oct;33(10):1667-73.
134 - Haussinger D, Roth E, Lang F, Gerok W. Cellular hydration state: an important determinant of protein catabolism in health and disease. Lancet. 1993 May 22;341(8856):1330-2.
135 - Ingwall JS. Creatine and the control of muscle-specific protein synthesis in cardiac and skeletal muscle. Circulation research. 1976 May;38(5 Suppl 1):I115-23.
136 - Demant TW, Rhodes EC. Effects of creatine supplementation on exercise performance. Sports medicine (Auckland, NZ. 1999 Jul;28(1):49-60.
137 - Lawler JM, Barnes WS, Wu G, Song W, Demaree S. Direct antioxidant properties of creatine. Biochemical and biophysical research communications. 2002 Jan 11;290(1):47-52.
138 - Green AL, Hultman E, Macdonald IA, Sewell DA, Greenhaff PL. Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans. The American journal of physiology. 1996 Nov;271(5 Pt 1):E821-6.
139 - Schoch RD, Willoughby D, Greenwood M. The regulation and expression of the creatine transporter: a brief review of creatine supplementation in humans and animals. Journal of the International Society of Sports Nutrition. 2006;3:60-6.
140 - Bloomer RJ. The role of nutritional supplements in the prevention and treatment of resistance exercise-induced skeletal muscle injury. Sports medicine (Auckland, NZ. 2007;37(6):519-32.
141 - Yasuda T, Sakamoto K, Nosaka K, Wada M, Katsuta S. Loss of sarcoplasmic reticulum membrane integrity after eccentric contractions. Acta physiologica Scandinavica. 1997 Dec;161(4):581-2.
142 - Konorev EA, Medvedeva NV, Dzhaliashvili IV, Stepanov VA, Saks VA. [Membranotropic effect of phosphocreatine and its structural analogs]. Biokhimiia (Moscow, Russia). 1991 Sep;56(9):1701-9.
143 - Warren GL, Fennessy JM, Millard-Stafford ML. Strength loss after eccentric contractions is unaffected by creatine supplementation. J Appl Physiol. 2000 Aug;89(2):557-62.
144 - Cooke MB, Rybalka E, Williams AD, Cribb PJ, Hayes A. Creatine supplementation enhances muscle force recovery after eccentrically-induced muscle damage in healthy individuals. Journal of the International Society of Sports Nutrition. 2009;6:13.
145 - Rawson ES, Conti MP, Miles MP. Creatine supplementation does not reduce muscle damage or enhance recovery from resistance exercise. Journal of strength and conditioning research / National Strength & Conditioning Association. 2007 Nov;21(4):1208-13.
146 - Rawson ES, Gunn B, Clarkson PM. The effects of creatine supplementation on exercise-induced muscle damage. Journal of strength and conditioning research / National Strength & Conditioning Association. 2001 May;15(2):178-84.
147 - Olsen S, Aagaard P, Kadi F, Tufekovic G, Verney J, Olesen JL, et al. Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training. The Journal of physiology. 2006 Jun 1;573(Pt 2):525-34.
148 - van Loon LJ, Murphy R, Oosterlaar AM, Cameron-Smith D, Hargreaves M, Wagenmakers AJ, et al. Creatine supplementation increases glycogen storage but not GLUT-4 expression in human skeletal muscle. Clin Sci (Lond). 2004 Jan;106(1):99-106.
149 - Santos RV, Bassit RA, Caperuto EC, Costa Rosa LF. The effect of creatine supplementation upon inflammatory and muscle soreness markers after a 30km race. Life sciences. 2004 Sep 3;75(16):1917-24.
150 - Noakes TD. Effect of exercise on serum enzyme activities in humans. Sports medicine (Auckland, NZ. 1987 Jul-Aug;4(4):245-67.
151 - Lev EI, Tur-Kaspa I, Ashkenazy I, Reiner A, Faraggi D, Shemer J, et al. Distribution of serum creatine kinase activity in young healthy persons. Clinica chimica acta; international journal of clinical chemistry. 1999 Jan;279(1-2):107-15.
152 - Janssen GM, Kuipers H, Willems GM, Does RJ, Janssen MP, Geurten P. Plasma activity of muscle enzymes: quantification of skeletal muscle damage and relationship with metabolic variables. International journal of sports medicine. 1989 Oct;10 Suppl 3:S160-8.
153 - Sorichter S, Mair J, Koller A, Gebert W, Rama D, Calzolari C, et al. Skeletal troponin I as a marker of exercise-induced muscle damage. J Appl Physiol. 1997 Oct;83(4):1076-82.
154 - Moran JH, Schnellmann RG. A rapid beta-NADH-linked fluorescence assay for lactate dehydrogenase in cellular death. Journal of pharmacological and toxicological methods. 1996 Sep;36(1):41-4.
155 - Bassit RA, Curi R, Costa Rosa LF. Creatine supplementation reduces plasma levels of pro-inflammatory cytokines and PGE2 after a half-ironman competition. Amino acids. 2008 Aug;35(2):425-31.
156 - Bassit RA, Pinheiro CH, Vitzel KF, Sproesser AJ, Silveira LR, Curi R. Effect of short-term creatine supplementation on markers of skeletal muscle damage after strenuous contractile activity. European journal of applied physiology. 2010 Mar;108(5):945-55.
157 - Hausswirth C, Lehenaff D. Physiological demands of running during long distance runs and triathlons. Sports medicine (Auckland, NZ. 2001;31(9):679-89.
158 - Neubauer O, Konig D, Wagner KH. Recovery after an Ironman triathlon: sustained inflammatory responses and muscular stress. European journal of applied physiology. 2008 Oct;104(3):417-26.
159 - Newham DJ, Mills KR, Quigley BM, Edwards RH. Pain and fatigue after concentric and eccentric muscle contractions. Clin Sci (Lond). 1983 Jan;64(1):55-62.
160 - Wood SA, Morgan DL, Proske U. Effects of repeated eccentric contractions on structure and mechanical properties of toad sartorius muscle. The American journal of physiology. 1993 Sep;265(3 Pt 1):C792-800.
161 - Percario S, Domingues SP, Teixeira LF, Vieira JL, de Vasconcelos F, Ciarrocchi DM, et al. Effects of creatine supplementation on oxidative stress profile of athletes. Journal of the International Society of Sports Nutrition. 2012;9(1):56.
162 - Rahimi R. Creatine supplementation decreases oxidative DNA damage and lipid peroxidation induced by a single bout of resistance exercise. Journal of strength and conditioning research / National Strength & Conditioning Association. 2011 Dec;25(12):3448-55.
163 - Kingsley M, Cunningham D, Mason L, Kilduff LP, McEneny J. Role of creatine supplementation on exercise-induced cardiovascular function and oxidative stress. Oxidative medicine and cellular longevity. 2009 Sep-Oct;2(4):247-54.
164 - Coco M, Perciavalle V. Creatine ingestion effects on oxidative stress in a steady-state test at 75% VO(2max). The Journal of sports medicine and physical fitness. 2012 Apr;52(2):165-9.
165 - Vary TC, Lynch CJ. Nutrient signaling components controlling protein synthesis in striated muscle. The Journal of nutrition. 2007 Aug;137(8):1835-43.
166 - Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006 Feb 10;124(3):471-84.
167 - Flati V, Pasini E, D'Antona G, Speca S, Toniato E, Martinotti S. Intracellular mechanisms of metabolism regulation: the role of signaling via the mammalian target of rapamycin pathway and other routes. The American journal of cardiology. 2008 Jun 2;101(11A):16E-21E.
168 - Ohanna M, Sobering AK, Lapointe T, Lorenzo L, Praud C, Petroulakis E, et al. Atrophy of S6K1(-/-) skeletal muscle cells reveals distinct mTOR effectors for cell cycle and size control. Nature cell biology. 2005 Mar;7(3):286-94.
169 - D'Antona G, Nisoli E. mTOR signaling as a target of amino acid treatment of the age-related sarcopenia. Interdisciplinary topics in gerontology. 2010;37:115-41.
170 - Smith K, Reynolds N, Downie S, Patel A, Rennie MJ. Effects of flooding amino acids on incorporation of labeled amino acids into human muscle protein. The American journal of physiology. 1998 Jul;275(1 Pt 1):E73-8.
171 - Smith K, Barua JM, Watt PW, Scrimgeour CM, Rennie MJ. Flooding with L-[1-13C]leucine stimulates human muscle protein incorporation of continuously infused L-[1-13C]valine. The American journal of physiology. 1992 Mar;262(3 Pt 1):E372-6.
172 - D'Antona G, Ragni M, Cardile A, Tedesco L, Dossena M, Bruttini F, et al. Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice. Cell metabolism. 2010 Oct 6;12(4):362-72.
173 - Biolo G, Tipton KD, Klein S, Wolfe RR. An abundant supply of amino acids enhances the metabolic effect of exercise on muscle protein. The American journal of physiology. 1997 Jul;273(1 Pt 1):E122-9.
174 - Volpi E, Ferrando AA, Yeckel CW, Tipton KD, Wolfe RR. Exogenous amino acids stimulate net muscle protein synthesis in the elderly. The Journal of clinical investigation. 1998 May 1;101(9):2000-7.
175 - Svanberg E, Moller-Loswick AC, Matthews DE, Korner U, Andersson M, Lundholm K. Effects of amino acids on synthesis and degradation of skeletal muscle proteins in humans. The American journal of physiology. 1996 Oct;271(4 Pt 1):E718-24.
176 - Svanberg E, Zachrisson H, Ohlsson C, Iresjo BM, Lundholm KG. Role of insulin and IGF-I in activation of muscle protein synthesis after oral feeding. The American journal of physiology. 1996 Apr;270(4 Pt 1):E614-20.
177 - Preedy VR, Garlick PJ. The response of muscle protein synthesis to nutrient intake in postabsorptive rats: the role of insulin and amino acids. Bioscience reports. 1986 Feb;6(2):177-83.
178 - Lynch CJ, Halle B, Fujii H, Vary TC, Wallin R, Damuni Z, et al. Potential role of leucine metabolism in the leucine-signaling pathway involving mTOR. American journal of physiology. 2003 Oct;285(4):E854-63.
179 - Lynch CJ, Patson BJ, Anthony J, Vaval A, Jefferson LS, Vary TC. Leucine is a direct-acting nutrient signal that regulates protein synthesis in adipose tissue. American journal of physiology. 2002 Sep;283(3):E503-13.
180 - Biolo G, Maggi SP, Williams BD, Tipton KD, Wolfe RR. Increased rates of muscle protein turnover and amino acid transport after resistance exercise in humans. The American journal of physiology. 1995 Mar;268(3 Pt 1):E514-20.
181 - Phillips SM, Tipton KD, Aarsland A, Wolf SE, Wolfe RR. Mixed muscle protein synthesis and breakdown after resistance exercise in humans. The American journal of physiology. 1997 Jul;273(1 Pt 1):E99-107.
182 - Shimomura Y, Harris RA. Metabolism and physiological function of branched-chain amino acids: discussion of session 1. The Journal of nutrition. 2006 Jan;136(1 Suppl):232S-3S.
183 - Tipton KD, Ferrando AA, Phillips SM, Doyle D, Jr., Wolfe RR. Postexercise net protein synthesis in human muscle from orally administered amino acids. The American journal of physiology. 1999 Apr;276(4 Pt 1):E628-34.
184 - Brooks GA. Amino acid and protein metabolism during exercise and recovery. Medicine and science in sports and exercise. 1987 Oct;19(5 Suppl):S150-6.
185 - Nosaka K, Sacco P, Mawatari K. Effects of amino acid supplementation on muscle soreness and damage. International journal of sport nutrition and exercise metabolism. 2006 Dec;16(6):620-35.
186 - Jackman SR, Witard OC, Jeukendrup AE, Tipton KD. Branched-chain amino acid ingestion can ameliorate soreness from eccentric exercise. Medicine and science in sports and exercise. 2010 May;42(5):962-70.
187 - Shimomura Y, Inaguma A, Watanabe S, Yamamoto Y, Muramatsu Y, Bajotto G, et al. Branched-chain amino acid supplementation before squat exercise and delayed-onset muscle soreness. International journal of sport nutrition and exercise metabolism. 2010 Jun;20(3):236-44.
188 - Pellegrino MA, Brocca L, Dioguardi FS, Bottinelli R, D'Antona G. Effects of voluntary wheel running and amino acid supplementation on skeletal muscle of mice. European journal of applied physiology. 2005 Mar;93(5-6):655-64.
189 - Greer BK, White JP, Arguello EM, Haymes EM. Branched-chain amino acid supplementation lowers perceived exertion but does not affect performance in untrained males. Journal of strength and conditioning research / National Strength & Conditioning Association. 2011 Feb;25(2):539-44.
190 - Matsumoto K, Koba T, Hamada K, Sakurai M, Higuchi T, Miyata H. Branched-chain amino acid supplementation attenuates muscle soreness, muscle damage and inflammation during an intensive training program. The Journal of sports medicine and physical fitness. 2009 Dec;49(4):424-31.
191 - Koba T, Hamada K, Sakurai M, Matsumoto K, Hayase H, Imaizumi K, et al. Branched-chain amino acids supplementation attenuates the accumulation of blood lactate dehydrogenase during distance running. The Journal of sports medicine and physical fitness. 2007 Sep;47(3):316-22.
192 - Matsumoto K, Mizuno M, Mizuno T, Dilling-Hansen B, Lahoz A, Bertelsen V, et al. Branched-chain amino acids and arginine supplementation attenuates skeletal muscle proteolysis induced by moderate exercise in young individuals. International journal of sports medicine. 2007 Jun;28(6):531-8.
193 - Stock MS, Young JC, Golding LA, Kruskall LJ, Tandy RD, Conway-Klaassen JM, et al. The effects of adding leucine to pre and postexercise carbohydrate beverages on acute muscle recovery from resistance training. Journal of strength and conditioning research / National Strength & Conditioning Association. 2010 Aug;24(8):2211-9.