Accepted Manuscript

Branched chain amino acid supplementation and exercise induced muscle damage in
exercise recovery: a meta-analysis of randomized clinical trials

Mohammad Hossein Rahimi, Sakineh Shab-Bidar, Mehdi Mollahosseini, Kurosh

Djafarian

PII: S0899-9007(17)30095-3
DOI: 10.1016/j.nut.2017.05.005
Reference: NUT 9961

To appear in: Nutrition

Received Date: 11 January 2017

Revised Date: 14 April 2017
Accepted Date: 8 May 2017

Please cite this article as: Rahimi MH, Shab-Bidar S, Mollahosseini M, Djafarian K, Branched chain
amino acid supplementation and exercise induced muscle damage in exercise recovery: a meta-analysis
of randomized clinical trials, Nutrition (2017), doi: 10.1016/j.nut.2017.05.005.

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 ACCEPTED MANUSCRIPT
Branched chain amino acid supplementation and exercise induced muscle damage in

exercise recovery: a meta-analysis of randomized clinical trials

Mohammad Hossein Rahimi1, Sakineh Shab-Bidar1 , Mehdi Mollahosseini 1, Kurosh

Djafarian*3

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1
Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran

University of Medical Sciences (TUMS), Tehran, Iran

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3
Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran

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University of Medical Sciences, Tehran, Iran

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*Corresponding author:
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Kurosh Djafarian, No 44, Hojjat-dost Alley, Naderi St., Keshavarz Blvd, Tehran, Iran Tele:

+98218 89 55 975
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Email: kdjafarian@tums.ac.ir
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Short title: BCAA and muscle damage

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Abstract

Objective: Accumulating evidences suggest positive effects of BCAAs on moderate muscle

damage. However, findings vary substantially across studies. The aim of this review was to

examine the effect of branched chain amino acids (BCAA) on recovery following exercise

induced muscle damage (EIMD).

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Methods: Controlled trials were identified through computerized literature searching and

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citation tracking performed up to November 2015. To pool data, either a fixed-effects model

or a random-effects model and for assessing heterogeneity, Cochran's Q and I2 tests were

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used.

Results: Eight trials met the inclusion criteria. Pooled data from eight studies showed that

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BCAA significantly reduced Creatine Kinase (CK) at two follow-up time (<24 and 24 hours)
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in comparison with placebo recovery(<24h: MD= -71.55 U.L-1, 95% CI: -93.49 to -49.60, p<

0.000, n=5 trials and 24h: MD= -145.04 U.L-1, 95% CI: -253.66 to -36.43, p = 0.009 n=8
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trials). In contrast, effects were not significant in any of the follow-up times for muscle
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soreness (MS) and lactate dehydrogenase (LDH).

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Conclusion: The current evidence based information offer that BCAA is better than using

passive recovery or rest after various forms of exhaustive and damaging exercise. The
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advantages relate to a reduction in MS, and ameliorated muscle function because of an

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attenuation of muscle strength and muscle power loss after exercise.

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Introduction

The benefits of regular exercise to improve health and prevent chronic disease are well

known. However, exceptional and sudden exercise results in ambiguous pain in the skeletal

muscle within hours or days during recovery after exercise, which is referred to as delayed

onset muscle soreness (DOMS)[1]. DOMS is one of the symptoms of exercise induced

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muscle damage (EIMD). EIMD is defined as a decrease in neuromuscular function, reduced

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range of movement, increased muscle soreness (MS), limb swelling and the elevation of

intramuscular proteins in blood[2]. DOMS is commonly an unpleasant feeling and can

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adversely affect muscle efficiency from voluntary reduction of effort, as well as from the

muscles intrinsic loss of capacity to generate force[3]. Therefore, it is favorable to reduce

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exercise-induced DOMS not only in athletes but also in untrained individuals [4].
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Branched-chain amino acids (valine, leucine, and isoleucine; BCAAs) are abundant and
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catabolized in the skeletal muscle, help to prevent protein breakdown[5, 6] and elevate

protein synthesis[7]. The effects of BCAAs supplementation on increased plasma CK and

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lactate dehydrogenase (LDH) activity and DOMS have been controversial and the accounting
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factors of these differences remain unclear. Studies examining recovery from heavy

endurance activity[1, 8] have reported evidence that BCAA are advantageous in decreasing
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muscle damage and accelerating the recovery procedure and in a well-controlled example[9]
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MS was decreased with BCAA. It should be noticed that accumulating evidences suggest
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positive effects of BCAAs on moderate muscle damage. However, findings vary substantially

across studies. Therefore, we aimed to conduct a meta-analysis from randomized controlled

trials (RCTs) to specify the effects of BCAAs supplementation on MS and indirect markers

of muscle damage in all studies with this subject.

Methods

Search Strategy

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A computerized literature search was performed from inception to November 2015 using

MEDLINE, Sport Discus, Scopus and Google scholar. The following phrases and their

combinations were used: :"branched chain amino acid, muscle soreness, delayed onset of

muscle soreness, muscle damage, exercise, recovery strategy and recovery.

Reference lists of all articles were examined for identification of further eligible studies

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(Figure 1).

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Study inclusion and exclusion criteria

Studies must have involved human participants treated with a BCAA intervention after

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exercise or before and after exercise. Studies meeting the following criteria were

considered for inclusion: 1) the study design was randomized into an intervention group

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(BCAA) and a control group; 2) at least one outcome measure of muscle damage (CK, LDH
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or both) or visual analogue scale of muscle soreness were reported; 3) only outcome variables
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measured immediately(<24h), 24h, 48h, 72h or 96h post exercise were recorded; 4) BCAA

was applied before exercise, immediately post exercise and studies who repeated the
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supplementation protocol on subsequent days were included too and 5) participants could be
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male or female and of any athletic training status. There were no restrictions placed on the

type of exercise or control groups used. Studies using multiple supplementations, including
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BCAA in conjunction with another supplement, following EIMD were not considered.
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Selection of studies
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Two authors (MR and MM) independently elected trials for inclusion. The titles and abstracts

of papers received by the search strategy were screened. All trials categorized as relevant by

either of the authors were retrieved. On basis of the information within the full information,

we used a standardized form to select the trials eligible for inclusion in review. Contradiction

between the authors was solved by consensus, or third researcher (SS-b).

Data extraction

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Two reviewers independently performed the data extraction using a customized form and

settled differences by consensus. This was used to extract relevant data on methodological

design, eligibility criteria, interventions (including detailed characteristics of the BCAA

supplementation protocols), comparisons and outcome measures.

Measures of treatment effect

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For every study, mean differences and 95% confidence intervals were computed for

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continuous results. For continuous results that were pooled on different scales, standardized

mean differences were used. We had designed to preferentially extract data based on changes

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from baseline (mean change scores); however, most of studies reported follow-up scores. In

the cases that there was no evidence of heterogeneity of effect (P>0.1), a fixed-effect model

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was used for meta-analysis. In events where there was evidence of statistical heterogeneity,
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we checked the outcomes using a random-effects mode.
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Results

Included studies
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Characteristics of included studies are summarized in Table 1 that provides an overview of

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the number of participants and the methodological quality in each included trial. There were

15 eligible studies [1, 5, 9-19], and of them seven studies had cross-over designing and were
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excluded and finally eight studies remained for analysis. Data of some papers was not
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accessible because they were conducted years ago and author could not send us the data[1] or
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the author did not respond our request for data but we used some data that were in paper [9].

Percentage of weight for three articles [20-22] was %0 or near zero (0.01%) in five follow-up

times for CK , then we excluded those in analysis [12]. Therefore, the articles that were

included in all analysis were five. Moreover, if a study measured outcomes for different doses

of BCAA, we included each dose as a separate study in analysis [14, 17]. All healthy

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participants were men (n=70). Participants tended to be young and mean age of them was 23.

All eligible studies were randomized controlled trials.

Details of outcome

Soreness was the most commonly reported outcome. Five studies assessed MS via visual

analogue scale (VAS) [9-11, 13, 14]. The written descriptors used at each end of the scale

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were specified in all studies. Biochemical markers were reported in 7 studies [1, 10-14, 17].

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CK was reported in all studies and LDH in three studies [10, 14, 17].

Follow up

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All studies undertook multiple follow-up observations for each outcome. All studies reported

multiple follow-ups (e.g. post-exercise for intervention and placebo immediately, 1h, 2h, 24h,

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48h, 72h and 96h after exercise). One study had one follow-up time immediately after
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exercise [20] , one study reported immediately, 1h ,2h and 24h follow-up times [23], two
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studies had 24h and 48h follow-up times[17, 24] and four studies reported 24h, 48h, 72h and

96h after exercise [9, 19, 21, 22]. We focused on outcomes reported immediately after the
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completion of the recovery intervention and subsequent days (24h, 48h, 72h and 96h).
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Risk of Bias

No evidence of publication bias was detected for any of follow-up time by Eggers test with
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regard to the major effects of BCAA on muscle soreness, CK and LDH.

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Meta-analysis of Muscle soreness

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Four studies [9-11, 13] in this comparison presented data on MS based on VAS. Four RCTs

that studied the effect of BCAA (total sample size 80) on MS had sufficient data to make the

pooled analysis at 24 h and 48h. Pooled results were presented in five subcategories based on

follow-up times in Figure 2. In <24h just one study had data [21] and one study [9] had four

follow-up times but had reported two follow up times (48h and 72h) in the paper and we did

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not receive raw data from the authors. Pooled analysis showed that the overall effects were

not statistically significant in any of the follow-up times:

(48h; MD= -24.375 mm, 95% CI: -51.355 to 2.605, 4 trials and 72h; MD= -19.861 mm, 95%

CI: -43.620 to 3.899, 4 trials). The heterogeneity between the studies at 48h (I2 = 95 percent,

p<0.0001) and 72h (I2 = 84.8 percent, p<0.0001) made it difficult to clarify the true effect of

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BCAA after exercise-induced muscle soreness at 48h and 72h.

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The meta-analysis showed that BCAA applied during exercise is not effective on muscle

soreness in follow-up times but overall results indicated BCAA is beneficial after exercise

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(p = 0.008).

Meta-analysis of Muscle damage: CK

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Pooled results were presented in five subcategories based on follow-up times in Figure 3.
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There was significant positive effect of BCAA on CK in <24h and 24h follow-up times:

(<24h: MD= -71.55 U.L-1, 95% CI: -93.49 to -49.60, p = 0.000, n=5 trials and 24h: MD= -
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145.04 U.L-1, 95% CI: -253.66 to -36.43, p = 0.009 n=8 trials). Actually, three RCTs which
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studied the effect of BCAA had no sufficient data to make the meta-analysis possible at 48h.
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As the weight percent of one study[12] with time less than 24h and that of two studies with

follow-up times of 48h, 72h and 96h follow-up times in the meta-analysis was zero, those
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studies were excluded[10, 22]. Then one study remained [19] for 72h and 96h follow-up time
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which we did not show the result. The outcome of heterogeneity showed that the differences

observed between trials were unlikely to be caused by chance (p = 0.954; I2 = 0 percent) in

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<24h. However, the heterogeneity between the studies at 24h was high (p = 0.008; I2 = 63.4

percent).

Meta-analysis of Muscle damage: LDH

Three studies [11, 14, 17] had recorded LDH levels. Two studies have recorded LDH levels

for two doses[14, 17]. Pooled results from these five trials in 24h and three trials in 48h found

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no significant difference in all follow-up times: (24h; MD= -21.88 U.L-1, 95% CI: -49.78 to

6.02, 5 trials and 48h; MD= -16.29 U.L-1, 95% CI: -48.55 to 15.97, 3 trials). For <24h, 72h

and 96h we had just one trial per hours [22].

All the included studies, indicating little variability between studies that cannot be explained

by chance in 24h (I2 =0.0 %, p=1.000) and 48h (I2 =0.0 %, p=0.446).

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Discussion

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The efficacy of BCAA has not been distinctly established; therefore this meta-analysis has

provided insight into the potential advantages conferred by such interventions that allow

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trainers to make an informed decision on their efficacy and usage. In a review paper by

Sorichter S et al.,[25] it is reported that to assess the amount of skeletal muscle damage,

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plasma CK activity and plasma myoglobin levels are widely used as markers for muscle
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injury. However, this meta-analysis was performed on muscle soreness, CK and LDH
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because there is adequate data on these variables. Although CK and LDH are not only the

most used outcomes, but those are the two best markers of muscle damage [26-29].
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Therefore, the effect of BCAA interventions can be assessed by these three variables with
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some confidence. The main findings of this study were as follows: (1) BCAA did not

alleviate symptoms of DOMS statistically at 24, 48, 72 and 96 h post exercise. (2) BCAA had
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a significant effect in reducing efflux of CK post exercise. (3) BCAA had no effect on LDH
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efflux.
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BCAA resulted in no improvements in MS recovery in follow-up times separately compared

to control groups. This was based on pooled data at two time points (48 and 72 hours), with

findings upheld when a random-effects model was applied. It is important to consider the

overall relevance of these findings especially on significant reduction in DOMS. The positive

effects of BCAA on these symptoms could cause reductions in perceived MS regardless of

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measurement times. Of particular note, the results for all the trials were adjusted to fit the

same 200mm VAS.

Exercise-induced MS accompanies EIMD, and degrees of perceived MS are widely used to

evaluate BCAA effects during recovery, since it provides major information regarding the

condition of the muscle. Although it may not specifically reflect the amount of EIMD,

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because many factors are presumed to contribute to the perception of soreness [28]. DOMS

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are related to mechanical forces in the elastic tissue or contractile, that result in the muscle

fiber disruption and surrounding connective tissue [30], the inflammatory response [31]or a

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combination of both [32]. It has been suggested that inflammation of the perimysium may

cause the pain [33]. Active inflammatory cells are not always present with indications and

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symptoms of DOMS [27]. Moreover, the time course between pain and damage is
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controversial, as the inflammatory response starts as quickly as a few hours after tissue injury
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before muscles become painful [34] and the BCAA are unlikely to alleviate soreness via the

inflammatory pathway [9]. Therefore the underlying mechanisms behind the reason of
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DOMS remain obscure [26, 35].

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We observed significantly lower values of CK concentrations during <24 and 24 hours post

exercise with BCAA in comparison to passive recovery without any significant changes in
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LDH. In fact, this review confirms that BCAA has positive effects after EIMD; the evidence
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shows that supplementation administered before, immediately and at least 24h post-exercise
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decrease CK up to 24 h. LDH seems to be reduced, especially 24 hours following exercise.

However, the effect beyond this period is not shown for both markers. CK, a substitute index

of muscle damage, is more indicative of gaps in sarcolemma or damage and accordingly

causing the cytosolic enzymes to exude from the cell in to the blood [9]. However, the cell

membrane is likely to have undergone some degree of lipolysis as a result of an imbalance in

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calcium homeostasis [36], almost certainly from the exercise insult and we suppose that the

membrane integrity is maintained to greater extent by BCAA supplementation.

The responses of CK and LDH might depend on where the primary site of muscle damage

happened, the training situation of the participants [17, 37], the type and familiarity with the

exercise condition used, and therefore, the limit of myocellular release of specific proteins.

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The high intra- and inter-individual variation in CK and LDH response question its accuracy

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at scaling the value of muscle damage because these parameters rather than providing

evidence for its progression, mostly serve as indicators of recovery and as global markers for

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damage to contractile elements [5, 14, 38].

A complete search based on electronic databases and complementary sources was undertaken

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in the current meta-analysis. However, we acknowledge that some research (such as
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conference proceedings) may have been overlooked. There were a limited number of females
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in the reviewed studies. A significant gender effect observed in serum CK activity in other

studied [39]. The majority of studies evaluated pain using a visual analogue scale, ranging
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from 0 normal to 200 mm extremely sore). This provides a subjective measure of muscle
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soreness which is likely to relate to DOMS. We must acknowledge that in some of the

included studies, MS may have a more complex etiology and other reasons of post exercise
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muscle pain may have contributed to the result scores presented.

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Many factors can influence the inconclusive findings and the high heterogeneity stated. The
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variations in BCAA classifications between countries, different manufacturers of BCAA,

percent of leucine, isoleucine and valine, may also contribute to the inconsistencies between

results. Moreover, some athletes can be more or less sensitive to alterations in myocyte

membrane permeability, or have different biomarker clearance rates due to individual

responses to exercise and training situation. Moreover included studies in this review

reported different dosages ranging from 7 gr [21] to three dose of 32 gr per day [24].

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Therefore, further research with different dosage of BCAA (whenever was possible with a

placebo condition) is needed to identify the optimal dosage and repetition per day to better

recovery. It is also necessary to know the optimal length of time that BCAA must be applied.

Supplementation protocols in the studies were different. In some studies supplementation

conducted before exercise and continued after exercise[19, 21, 22] but some of them had not

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continued after exercise [1, 14, 17] or in some studies supplementation started with exercise

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protocol and before that there was not supplementation[9, 12]. Considering these issues and

due to the variation in muscle damage characteristics from one individual to another [10], the

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variability in responses to EIMD [4], the complex nature of EIMD [38, 40, 41], and the

inconsistent findings, limited practical recommendations can be reported. Nevertheless it

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seems that supplementation before study for at least one week and additional dose for
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exercise day with continues supplementation in follow up days is an appropriate protocol for
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beneficial usage.

Although, the current review focused on the use of BCAA in healthy people, some evidence
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suggests that other methods of supplementation (including combination with glucose [42] or
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other amino acids [43] is being used as a method of recovery following strenuous exercise.

This area should be systematically examined in future reviews.

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Finally, we have focused on important outcomes related to recovery including; muscle

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soreness and muscle damage makers. Other key correlates of athletic recovery, such as
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muscle function, inflammation, flexibility and neuromuscular function, are known to be

reduced following EIMD. Other reviews may also be required to assess these outcome

measures following various therapeutic recovery strategies.

Conclusion

To our knowledge this is the first systematic review and meta-analysis that aimed to evaluate

the effects of BCAA on athletic recovery following exercise. The current evidence based

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information offer that BCAA is better than using passive recovery or rest after various forms

of exhaustive and damaging exercise. The advantages relate to a reduction in MS, and

ameliorated muscle function because of an attenuation of muscle strength and muscle power

loss after exercise. The quality of these effects seems to be clinically relevant but may be

most applicable to elite sport.

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Acknowledgments: MHR and SS-b designed research. KDj provided conceptual input into

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the design of the study. MM and MHR collected the data. MHR and MM analyzed the data.

MM and SS-b interpreted the data. MM, SS-b, MHR and KDj contributed to the final

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manuscript preparation manuscript. All of the authors read and approved the final

manuscript. This research did not receive any specific grant from funding agencies in the

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public, commercial, or not-for-profit sectors. The authors declared no conflicts of interest.
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exercise-induced delayed onset muscle soreness in college-age females. ISRN nutrition,

2013. 2013.
[43]. Ra, S.G., et al., Additional effects of taurine on the benefits of BCAA intake for the delayed-
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onset muscle soreness and muscle damage induced by high-intensity eccentric exercise. Adv
Exp Med Biol, 2013. 776: p. 179-87.
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Table 1 .Summary of relevant sources of data included for meta-analysis

CK, creatine kinase. DOMS, delayed onset of muscle soreness. LDH, lactate dehydrogenase

Author(s) Participant Exercise Mean age Dose Number Total Outcome

(training intervention (gr) of Dose supplementation variables and
number),status per day Duration (day) time of
measurement

PT
post exercise
(h)
Four, A. 26 (Non Neuromuscular 23 7 1 1 CK (<2 ,24 ,48
[24] athlete) electrostimulation ,72 ,96)

RI
exercise DOMS (<2 ,24
,48 ,72 ,96)
Ra, S. G. 18 (Non Eccentric elbow 22 3.2 3 14 CK (<2 ,24 ,48

SC
[25] athlete) extension ,72 ,96)
LDH (<2 ,24
,48 ,72 ,96)
Knechtle, B. 28 (Athlete) Marathon 43 0.25 80 1 CK (1)

U
[22]
AN
Howatson, 12 (Athlete) Drop-jump 23 10 2 9 CK (24 ,48 ,72
G. [21] ,96)
DOMS (24 ,48
,72 ,96)
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Ramin, A. 19 (Athlete) Heavy resistance 22 32 3 7 CK (24 ,48)

[23] LDH (24 ,48)
1
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Ramin, A. 19 (Athlete) Heavy resistance 22 15 3 7 CK (24 ,48)

[23] LDH (24 ,48)
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Mohamad- 20 (Athlete) Soccer 20 32 3 7 CK (24 ,48)

Panahi, LDH (24 ,48)
EP

Payam [16]
1

Mohamad- 20 (Athlete) Soccer 20 15 3 7 CK (24 ,48)

Panahi, LDH (24 ,48)
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Payam [16]
2
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Jackman, 24 Eccentric - 7.3 4 3 CK (<2h, 24,

Sarah [8] exercise 48, 72)
DOMS (<2h,
24, 48, 72)
Ghaderi 20 Eccentric 21 14 1 1 CK (<2h, 24)
[18] exercise
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Records identified through Additional records identified

Identification

database searching through other sources

(n=65) (n=5)

PT
Records after duplicated removed

RI
(n=45)
Screening

SC
Records screened Records

U
exclude
(n=45)
AN
(n=20)
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Full-text articles assessed for

Full-text article
eligibility
excluded by
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Eligibility

(n=25) reasons
TE

(n=10)
EP

Studies included in qualitative

Cross-over
synthesis
studies
C

(n=15)
(n=7)
AC
Included

Studies included in qualitative

synthesis

(meta-analysis)

(n=8)
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Figure 1. Summary of search strategy and selection process based on included and excluded studies.

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Highlights

BCAA significantly reduced Creatine Kinase (CK) up to 24 hours

BCAA had not beneficial effects in any of the follow-up times for muscle soreness (MS)
and lactate dehydrogenase (LDH)
BCAA is better than using passive recovery or rest after various forms of exhaustive and

PT
damaging exercise

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