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

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

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

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 acylcoenzyme 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 transmembrane 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

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

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

is unnecessary or prooxidant and thus potentially unsafe.

isoform of CPT-1 with low affinity for L-carnitine [80].

to low tissue concentrations [79, 87].

damage.

68 Muscle Injuries in Sport Medicine

**4. Carnitine**

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]. 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 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 hypoxiainduced fatigue in electrically stimulated rat skeletal muscle in vitro through its key stimula‐ tory 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 conse‐ quence 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]. Further‐ more 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.

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

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

http://dx.doi.org/10.5772/56590

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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

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 supple‐ mentation in reducing the severity of exercise-induced muscle damage and/or promote

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 supple‐ mentation 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

recovery following strength training and endurance paradigms [140].

of creatine has been found in a variety of endurance exercise paradigms [127-129].

g/day for a period of several weeks [138, 139].

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.
