**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 recogni‐ tion, 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.

tation 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 supple‐ mentation strategy in maintaining muscle integrity after intense prolonged exercise. The

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

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

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 recogni‐ tion, 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

mechanisms underlying such a protective effect are only partially known.

**6. Essential amino acids**

74 Muscle Injuries in Sport Medicine

induced muscle injuries.

completed protein is released from the ribosome [165].

eukaryotic elongation factor 2 kinase (eEF2k) [169].

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 partic‐ ular 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 exercisetriggered 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 immedi‐ ately 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 perform‐ ance 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].

protective effects of BCAA supplementation on muscle damage deserve further investigations,

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

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

77

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

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 signal‐ ling paths thereby unfavorably affecting muscle function, performance, and recovery from

Department of Molecular Medicine and Interdepartmental Research Centre in Motor Activi‐

[1] Hough T. Ergographic Studies in Muscular Fatigue and Soreness. Journal. 1900 Nov

[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.

[3] Ciciliot S, Schiaffino S. Regeneration of mammalian skeletal muscle. Basic mecha‐ nisms and clinical implications. Current pharmaceutical design. 2010;16(8):906-14.

[4] Allen DG. Eccentric muscle damage: mechanisms of early reduction of force. Acta

Scandinavian journal of medicine & science in sports. 2003 Apr;13(2):88-97.

physiologica Scandinavica. 2001 Mar;171(3):311-9.

to be mostly oriented on unraveling the effects of supplements on inflammation.

**7. Conclusions**

injury.

**Author details**

Giuseppe D'Antona\*

**References**

20;5(3):81-92.

Address all correspondence to: gdantona@unipv.it

ties (CRIAMS), University of Pavia, Italy

lengthening, contractions.

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. Con‐ sidering 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.
