**3. Antioxidant/vitamines**

Nutritional antioxidants are non enzymatic compounds including the lipid-soluble vita‐ min 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 pre‐ vent their transformation into more highly reactive forms, having intracellular and extrac‐ ellular sites of action [22].

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 associ‐ ated 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

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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 supplemen‐ tation 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 perox‐ idation and inflammatory response [56]. In another study combination of vitamin C with nacetylcysteine 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

Overall, although conflicting results on the topic may result from ununiformities of supple‐ mentation 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.

exercise induced muscle damage.

been not confirmed by others [54, 55].

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 mito‐ chondria 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 associ‐ ated 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].

**3. Antioxidant/vitamines**

66 Muscle Injuries in Sport Medicine

ellular sites of action [22].

the inflammation mainly by neutrophils.

Nutritional antioxidants are non enzymatic compounds including the lipid-soluble vita‐ min 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 pre‐ vent their transformation into more highly reactive forms, having intracellular and extrac‐

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 mito‐ chondria during mitochondrial phosphorylation and via xanthine oxidase metabolism in the capillary endothelium [25, 26] whereas the main secondary source of ROS is generated during

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

*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 supplemen‐ tation 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 perox‐ idation and inflammatory response [56]. In another study combination of vitamin C with nacetylcysteine 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 supple‐ mentation 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.

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]. Accord‐ ingly most studies showed improved maximum oxygen consumption, reduced lactate accumulation, and increased high-intensity exercise performance in professional and nonpro‐ fessional 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

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supplementation following on high-intensity training programs [96-101].

of high-repetition squat exercise in elderly individuals [106].

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

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]. Lcarnitine supplementation has been related to reduced postexercise CK [102, 103] and myo‐ globin [103, 105] concentrations suggesting that reduced oxidative stress may play a role in a

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.
