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Fasting \u0026 Fat Loss - Negative Effects of Branch Chain Amino Acids (BCAAs) - Thomas DeLauerBCAA and muscle damage prevention -
Amino acids AA are the building blocks of body protein. Further, some data suggest that BCAA supplementation can reduce exercise-induced muscle damage EIMD and muscle soreness after exercise. However, there is no consensus regarding the optimal amount of BCAA that an individual should consume to reduce EIMD and soreness.
The muscle damaging exercise involved 3 sets of 15 repetitions of ECC elbow muscle extension. Only 4 completed all data collection due to COVID Our data suggest that BCAA supplementation can reduce both EIMD and muscle soreness.
More research is needed to establish the optimal dose for BCAA consumption for different types of exercise. Lee, Crystal, "Effects of Branched-Chain Amino Acid Supplementation on Exercise Induced Muscle Damage and Delayed Onset of Muscle Soreness after a Bout of Eccentric Exercise" Electronic Thesis and Dissertation Repository.
Sports Sciences Commons. Advanced Search. Home About FAQ My Account Accessibility Statement Privacy Copyright. Varnier M, Sarto P, Martines D, Lora L, Carmignoto F, Leese G et al Effect of infusing branched-chain amino acid during incremental exercise with reduced muscle glycogen content.
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J Appl Physiol 89 6 — Maughan RJ, Gleeson M The biochemical basis of sports performance. Oxford University Press, Oxford. Download references. The authors are indebted to all the researchers whom we cited in this review for their significant and valuable research.
This work was financially supported by a grant 97s32 from Vice-Chancellor for Research Affairs of Ahvaz Jundishapur University of Medical Sciences. Nutrition and Metabolic Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. Department of Nutrition, Faculty of Allied Medical Sciences, Ahvaz Jundishapur University of Medical Sciences, P. BOX, , Ahvaz, Khuzestan, Iran. You can also search for this author in PubMed Google Scholar.
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Hormoznejad, R. Effect of BCAA supplementation on central fatigue, energy metabolism substrate and muscle damage to the exercise: a systematic review with meta-analysis. Sport Sci Health 15 , — Download citation. Received : 07 January Accepted : 01 March Published : 15 March Issue Date : 01 August Anyone you share the following link with will be able to read this content:.
Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Abstract Background and aims : Current state of evidence recommends beneficial effects of branched chain amino acids BCAAs on exercise performance; however, randomized controlled trials RCTs of BCAA supplementation yield discordant results.
Access this article Log in via an institution. References Coombes JS, McNaughton LR Effects of branched-chain amino acid supplementation on serum creatine kinase and lactate dehydrogenase after prolonged exercise.
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J,K Changes of M1 polarization with 2-DG, a glycolysis inhibitor. Hypoxia-inducible factor 1α HIF1α , a transcriptional factor targeted by mTORC1, controls glycolysis and M1 polarization Wang et al.
BCAAs increased the protein level of HIF1α during M1 polarization Figures 5B,C. Rapamycin abolished the BCAA-induced HIF1α and glycolytic enzymes expression HK2, PFK1 and LDHA Figures 5B,G—I.
Furthermore, 2-DG, the inhibitor of glycolysis, attenuated the mRNA levels of TNF-α and iNOS induced by BCAA Figures 5J,K , suggesting a weakened M1 polarization. Collectively, these data demonstrated that BCAAs promoted M1 polarization via activating the mTORC1-HIF1α-glycolysis pathway. We also explored how BCAA promoted M2 polarization.
Lipid metabolic reprogramming is essential for M2 polarization van den Bosch et al. mTORC1 and its downstream transcription factor PPARγ are key regulators of lipid metabolism in M2 polarization. We then investigated the role of mTORC1 and PPARγ in the BCAA-promoted M2 polarization.
As expected, BCAAs enhanced the activity of mTORC1 and the protein level of PPARγ during M2 polarization Figures 6A,B. Interestingly, rapamycin abolished the BCAA-induced mTORC1 activation and PPARγ expression Figure 6C , but showed no effect on BCAA-promoted M2 polarization Figures 6D—F.
Collectively, these data suggested that BCAAs promoted M2 polarization independent of the mTORC1-PPARγ pathway. FIGURE 6. BCAAs promote M2 polarization independent of the mTORC1-PPARγ pathway. A—C BCAAs μm enhanced the expression of PPARγ and mTORC1 activity during M2 polarization, and the effect of RAPA rapamycin, mTORC1 inhibitor on the expression of PPARγ.
D—F The effect of RAPA on the change in M2 polarization. Data are expressed as mean ± SEM. In the present study, we demonstrated BCAA supplementation promotes the repair of EIMD via enhancing macrophage polarization.
M1 and M2 macrophages stimulate the proliferation and differentiation of muscle satellite cells, respectively. Previous studies have shown that BCAA supplementation alleviate the level of CK and muscle soreness following EIMD in human. In the present study, our results also indicated that BCAA supplementation reduce the level of CK and accelerate the recovery of damaged muscle fibers, which is consistent with previous studies Fouré and Bendahan, ; Doma et al.
Kato et al. This phenomenon suggested that BCAA-improved EIMD may be related to inflammation. Previous studies indicated that macrophages play an important role during skeletal muscle repair Juhas et al.
There is no relevant study on whether BCAA intervention affect macrophage polarization during EIMD. Our results showed that BCAA enhances M1 and M2 polarization during skeletal muscle repair in different time stages, meanwhile, similar changes in the serum levels of inflammatory factors were observed in vitro.
These data suggested that macrophage polarization plays an important role in BCAA-induced muscle repair. In addition, skeletal muscle repair is a complex biological process, the activation, proliferation, and differentiation of SCs provides the potential capacity to muscle repair La et al.
In the current study, our results showed that BCAA supplementation promotes the proliferation and differentiation of skeletal muscle SCs, which is consistent with previous study Duan et al. However, Kato et al. This discrepancy could be attributed to the different muscle damage models.
Further experiments are warranted to analyze the differences between these two muscle damage models. Our results show BCAAs promote M1 and M2 polarization of macrophages, which further promote the proliferation and differentiation of SCs, respectively. Previous studies have reported that the pro-inflammatory and anti-inflammatory factors promote the proliferation and differentiation of SCs, respectively Akahori et al.
It can be speculated that BCAA-promoted pro- and anti-inflammatory factors mediate the stimulation of SC proliferation and differentiation from M1 and M2 macrophages. Meanwhile, other possible mechanisms should also be considered. The repair process of skeletal muscle involves a variety of cell types, such as macrophages and SCs Tidball, It is not entirely clear how macrophages and SCs work together to promote skeletal muscle repair.
Shang et al. Due to the important relationship between BCAA and glutamine, we speculate that glutamine may play an important role in BCAA-promoted macrophages stimulating SCs and muscle repair. mTOR signaling pathway is an important link between immune response and cell metabolism, moreover, mTORC1 is an important factor in sensing intracellular amino acid concentration Kang and Kumanogoh, Previous studies show that mTORC1 plays an inconsistent role in M2 polarization.
One study indicates that IL-4 stimulated bone marrow-derived macrophages BMDM from TSC1 knockout mice, which increased mTORC1 activity, M2 polarization weakened Byles et al.
However, two other studies showed IL-4 stimulated BMDM with mTOR inhibition Torin1 or Raptor knockout mice decreased mTORC1 activity , M2 polarization weakened Covarrubias et al. The reasons may be related to different the knockout mice model.
In addition, Covarrubias et al. This phenomenon suggests the metabolism in M2 polarization is not only lipid metabolism and may also involve glycolysis. Therefore, further experiments are warranted to explore the mechanism how BCAA regulates M2 polarization.
It has been shown that there is a wide spectrum of macrophage activation states in vivo Murray et al. An expanded range of stimuli can drive macrophage activation with distinct activation profiles in different directions Kang and Kumanogoh, In the current study, we used chemically activated macrophages to investigate the effect of BCAA on macrophage polarization in vitro.
The results of cultured cells were consistent with the expression of macrophage activation markers in vivo. Whether the macrophage polarization in vitro accurately recapitulates the changes of macrophages in vivo remains to be fully determined.
Staining of different types of macrophages in the damaged muscle may be of help. The current study demonstrated that BCAAs promoted C2C12 proliferation and differentiation via enhancing the macrophage polarization in vitro.
On the other hand, when BCAAs intake was increased in vivo , the SCs were exposed to a large number of factors, including the elevated BCAAs and inflammatory factors. Whether BCAAs exert direct impacts on myoblasts remains to be investigated. It is also possible that there are additive impacts from elevated BCAAs and inflammatory factors.
Nevertheless, our data show that macrophages mediate, at least partially, the impacts of BCAAs on SCs and thus the repair of EIMD. One limitation of our study is that, although we demonstrate that BCAAs promote the function of SCs via macrophages in cultured cells, direct evidence for this occurring in vivo is lacking, which could be provided by macrophage depletion animal model and the staining for SCs to assess their numbers in the damaged muscle.
In summary, the current study shows that BCAAs improve EIMD repair by promoting the proliferation and differentiation of muscle SCs through macrophage polarization.
The results highlight the critical role of macrophage in BCAA-induced repair of EIMD and indicate new approaches for the treatment of muscle-related diseases. The raw data supporting the conclusion of this article will be made available by the authors, without undue reservation.
The animal study was reviewed and approved by the Animal Research Ethics Committee of Beijing Sport University. YD, XZ, HS, and JQ designed the study. YD, WC, and HW performed the in vitro experiments. YD, XZ, and WJ performed in vivo experiments.
XZ, YY, and RG contributed to data analysis. YD drafted the manuscript. HS and JQ reviewed and edited the manuscript. All authors have read and agreed to the published version of the manuscript.
This work was supported by the National Key Research and Development Program of China YFA , the National Natural Science Foundation of China , , , , the Fundamental Research Funds for the Central University YB, QN , the Collaborative Innovation Program of Shanghai Municipal Health Commission CXJQ01 , the Scientific Research Fund of Shanxi Datong University K33 , and the Tianjin Key Medical Discipline Specialty Construction Project TJYXZDXKA.
The authors gratefully acknowledge the excellent assistance of Yunlong Shi, Yan Chen, and Yan Cheng. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Dxmage amino wnd Heart health awareness are Heart health awareness group of three essential amino acids:. BCAA supplements are commonly taken to boost muscle growth and enhance exercise performance. They may also help with weight loss and reducing fatigue after exercise. This article contains all the most important information about branched-chain amino acids and their benefits. These amino acids are grouped together because they are the only three amino acids to have a chain that branches off to one side.
The repair of exercise-induced muscle damage EIMD is closely Healthy alternatives for cravings with preventionn. Branched-chain amino acids BCAAsCognitive abilities testing a nutritional prefention, promote EIMD repair; however, the underlying mechanism remains unclear.
Protein expression of macrophages CD68 musclf CD and myogenic BCAA and muscle damage prevention factors MYOD and MYOG in gastrocnemius was analyzed. Inflammatory cytokines and creatine kinase CK levels in serum was also measured. In pfeventionperitoneal macrophages from mice were incubated with lipopolysaccharide LPS or IL-4 with or without BCAAs in culture medium.
For co-culture experiment, Da,age cells were cultured with the prevenrion medium from macrophages mhscle with LPS or IL-4 in the presence or absence of BCAAs. In addition, BCAA-promoted M1 macrophages further stimulated the proliferation prevvention muscle satellite preveniton, whereas Preventin M2 macrophages stimulated their differentiation.
Prevdntion intensity or unaccustomed strenuous exercise can cause exercise-induced ane damage BCAA and muscle damage prevention. The main symptoms musxle EIMD are the loss of muscle function and delayed onset muscle soreness Peake, The repair of EIMD mainly relies on muscle stem cells, ptevention satellite cells SCs.
After skeletal muscle damage, SCs proliferate and differentiate by expressing sequential transcription factors, such as Paired box7 Pax7Myogenic factor 5 Myf5Myoblast determination protein MYODand Myogenin MYOG Scala et BCAA and muscle damage prevention.
Pax7 maintains the muslce state of SCs. Myf5 and MYOD mainly regulate SCs musxle, whereas MYOG controls SCs differentiation Zammit, Understanding the mechanism underlying skeletal muscle prevdntion and finding intervention strategies are important for accelerating the recovery process from EIMD.
Studies suggest the EIMD-induced inflammatory response muslce an integral part of the damafe process Fatouros and Jamurtas, Macrophages, with their dammage responses, play an important role in promoting eamage muscle repair Markus et al. BCAA and muscle damage prevention, macrophages divide into two types: The classically activated Pprevention macrophages and the qnd activated M2 macrophages.
Dakage macrophages BCAA and muscle damage prevention present in the pro-inflammatory period of Miscle and associated with SCs proliferation Cleanse and detoxify Heart health awareness al.
Importantly, M1 and M2 macrophages prevejtion different metabolic programs to support energy Diabetic coma in elderly. M1 macrophages are mainly Endurance fuel supplements on glycolysis metabolism, Body shaming and eating disorders by HIF1α Wang et al.
This suggests that macrophage metabolism and polarization are closely linked, and macrophage polarization may be regulated by metabolic pathways.
Human studies have shown that Branched-Chain Amino Muscld BCAAs preventin is an effective approach muslce accelerate the recovery from EIMD Rahimi et preention.
BCAAs, including leucine, isoleucine, and valine, are essential amino acids for Packed with Orange Flavor. BCAA, amd leucine, activates the mammalian target of BCAA and muscle damage prevention complex dajage mTORC1a central pprevention node that exerts widespread control BCAA cellular metabolism and camage Wolfson and Energy conservation tips, Mammalian target of rapamycin mTOR preventin an important role in the macrophages function by regulating gene expression Cranberry vinegar recipes the annd and translational levels Kang and Kumanogoh, In recent BCAA and muscle damage prevention, BCAAs have been closely linked with glucose and lipid metabolism in metabolic and cardiovascular diseases Wang damafe al.
As a nutritional supplement, Ane reduce muscle dsmage and the level xnd muscle damage biomarkers Matsumoto et al. However, vamage underlying damahe remains to be fully understood. In this damxge, we established an EIMD model musdle explored the role of macrophages in BCAA alleviated skeletal muscle damage.
Muwcle addition, mhscle further explored the mechanism of BCAA regulated BAA polarization and musvle effect of BCAA-intervened macrophages on satellite cells. Male Sprague—Dawley rats 8-week-old; Charles River Laboratories China, Inc.
The protocol was approved by the Animal Research Ethics Committee of Beijing Sport University. On the day of eccentric exercise, BCAA supplement was administered immediately after the exercise.
All animals in the placebo group PLA received distilled water by oral gavage once a day over the same period. For the exercise group, 8 rats from each group were sacrificed at each time point of 1, 3, 5, and 7 days after the eccentric exercise.
The gastrocnemius muscle and blood were collected at various time points. The serum was collected from abdominal aorta of rats at each indicated time.
The final signals were read using a pan-wavelength micro plate reader BioTek Instruments, United States. For immunohistochemical analysis, the sections were adhered to poly-L-lysine-coated slides.
Further, the sections were deparaffinized and fixed in 0. Primary peritoneal macrophages M0 were isolated from mice as previously described Bisgaard et al. After 3 days, mouse was euthanized by cervical dislocation. The peritoneal fluid was collected and centrifuged for 10 min at 1, rpm in a refrigerated centrifuge.
The cell pellet was resuspended in DMEM medium and cells were cultured for 4—6 h at 37°C, during which the peritoneal macrophages attached to culture plates, allowing their separation from other types of cells.
Subsequently, non-adherent cells were removed by gently washing 3 times with warm PBS. M1 and M2 macrophages were obtained by incubating with LPS 0.
Macrophages were treated with different concentrations of BCAAs as previously described Lian et al. Cells were treated with 2-deoxy-D-glucose Liu et al. M0 macrophages were stimulated with LPS or IL-4 in the presence or absence of BCAAs in culture medium for 24 h, respectively. C2C12 cells proliferation was assessed by Cell Counting Kit-8 CCK8, Dojindo, Japan.
The measurement was done using a pan-wavelength micro plate reader BioTek Instruments, United States at nm. The total RNA were extracted from cells using Trizol reagent Invitrogen, United States and reverse transcribed into cDNA using RT SuperMix kit Promega, United States.
Real-time quantitative PCR q-PCR was performed using SYBR Green PCR mix ABI, United States and real-time PCR system Bio-Rad with the primer sequences in Table 1. All values are expressed as mean ± SEM. To explore the effect of BCAAs on EIMD, we established a rat model with EIMD, and treated the rats with or without BCAAs.
The muscle fibers of the gastrocnemius in the PLA group showed varying degrees of swelling and dilated intercellular space after EIMD Figures 1A,B. Moreover, the serum CK levels were increased after EIMD Figure 1C.
These changes indicated that the EIMD model was successfully constructed. Importantly, with BCAA treatment, the muscle fiber swelling was decreased on the first day after EIMD Figure 1B and the serum CK level was lower at the fifth and seventh day after EIMD Figure 1Ccompared with those in the PLA group.
Meanwhile, the expression of SCs proliferation marker MYOD was increased in BCAA group Figure 1D. In addition, BCAA advanced the peak expression of another SCs differentiation marker MYOG by 2 days, indicating that BCAA supplementation accelerated the repair of EIMD Figure 1E.
Collectively, these data demonstrated that BCAA supplementation promoted EIMD repair, consistent with previous studies Kato et al. FIGURE 1. Branched-chain amino acids BCAAs promote the repair of exercise-induced muscle damage EIMD.
B The effect of BCAAs on the cross-sectional area of gastrocnemius fibers in rats with EIMD. C The effect of BCAAs on serum CK levels in rats with EIMD.
D,E The effect of BCAAs on the proliferation MYOD and differentiation MYOG of the gastrocnemius satellite cells SCs in rats with EIMD. Data are presented as mean ± SEM. Immunohistochemical results revealed that BCAAs enhanced the protein expression of CD68 M1 and CD M2 during EIMD repair Figures 2A—D.
BCAA advanced the peak expression of CD68 by 2 days, suggesting that BCAAs accelerated macrophages M1 polarization during EIMD repair. Meanwhile, BCAAs increased the serum levels of proinflammatory cytokine IL-6 in the early stage of EIMD repair Figure 2E and the serum levels of anti-inflammatory cytokines IL in the late stage Figure 2F.
Collectively, these data suggested that BCAAs promoted both M1 and M2 polarization of macrophages during EIMD repair. FIGURE 2. BCAAs promote M1 and M2 polarization of macrophages during EIMD repair.
E,F The effects of BCAAs on serum levels of inflammatory cytokines, namely, IL-6, and IL during EIMD repair. We analyzed the direct effects of BCAAs on the polarization of M1 macrophages in vitro. We isolated the primary peritoneal macrophages from mice and exposed them to LPS with or without BCAAs in culture medium.
FIGURE 3. BCAA-promoted M1 macrophages enhance the proliferation of SCs. A—C The effects of various concentrations of BCAAs on the polarization of M1 macrophages.
D,E The effect of BCAA μm -treated M1 macrophages on C2C12 proliferation. It has been suggested that M1 macrophage affects SCs proliferation Minari and Thomatieli-Santos, We then tested whether the conditioned medium from M1 macrophages treated with BCAA could enhance SCs proliferation.
To do so, M0 macrophages were prestimulated with LPS with or without BCAA for 24 h. Fresh medium was then added to the M1 macrophages for 12 h and collected as conditioned media. C2C12 cells were then cultured with these conditioned media for 24 or 48 h. As expected, medium from M1 macrophages promoted the mRNA expression of Myf5, which is further enhanced by BCAA-promoted M1 macrophages Figure 3D.
Further, we analyzed the proliferation of C2C12 cells cultured with conditioned medium using the CCK8 kit. The result showed that the conditioned medium from prestimulated M1 macrophages promoted C2C12 cells growth, which was further enhanced by the conditioned medium from BCAA-treated M1 macrophages Figure 3E.
Collectively, these data suggested that BCAA-promoted M1 macrophages could enhance the proliferation of SCs.
We also explored the direct effects of BCAAs on the polarization of M2 macrophages in vitro. The primary peritoneal macrophages were isolated from mice and exposed to IL-4 with or without BCAAs in culture medium.
FIGURE 4. BCAA-promoted M2 macrophages enhance the differentiation of SCs. A—C The effect of BCAAs μm on M2 polarization of macrophages. D,E The effect of BCAA μm -treated M2 macrophages on C2C12 differentiation. It has been suggested that M2 affects SC differentiation Minari and Thomatieli-Santos, We then tested whether the conditioned medium from BCAA-promoted M2 macrophages could affect SCs differentiation.
C2C12 cells were cultured with differentiation medium and conditioned media from M2 or BCAA-treated M2 for 24 or 48 h.
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Cockburn E, Stevenson E, Hayes PR, Robson-Ansley P, Howatson G: Effect of milk-based carbohydrate-protein supplement timing on the attenuation of exercise-induced muscle damage. Appl Physiol Nutr Metab. Shimomura Y, Murakami T, Nakai N, Nagasaki M, Obayashi M, Li Z, Xu M, Sato Y, Kato T, Shimomura N, Fujitsuka N, Tanaka K, Sato M: Suppression of glycogen consumption during acute exercise by dietary branched-chain amino acids in rats. Download references. School of Life Sciences, Northumbria University, Newcastle upon Tyne, UK. School of Environmental Sciences and Development, Northwest University, Potchefstroom, South Africa. You can also search for this author in PubMed Google Scholar. Correspondence to Glyn Howatson. GH, as the principal investigator, contributed to conception and design of the experiment, data collection and analysis, data interpretation, manuscript draft and the editorial process. MH, as a post-graduate student, was responsible for conception, participant recruitment, data collection, initial data analysis, interpretation and initial drafting of the manuscript. SG contributed to data interpretation, data presentation and manuscript drafting and editing. JT, PGB, DNF contributed to data analysis, data interpretation and manuscript editing. All authors approved the final version of the manuscript. Open Access This article is published under license to BioMed Central Ltd. Reprints and permissions. Howatson, G. et al. Exercise-induced muscle damage is reduced in resistance-trained males by branched chain amino acids: a randomized, double-blind, placebo controlled study. J Int Soc Sports Nutr 9 , 20 Download citation. Received : 09 February Accepted : 08 May Published : 08 May Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Download ePub. Abstract Background It is well documented that exercise-induced muscle damage EIMD decreases muscle function and causes soreness and discomfort. Results A significant time effect was seen for all variables. Conclusion The present study has shown that BCAA administered before and following damaging resistance exercise reduces indices of muscle damage and accelerates recovery in resistance-trained males. Figure 1. Full size image. Figure 2. Figure 3. Figure 4. Discussion The initial aim of the present study was to examine the effects of BCAA supplementation on indices of muscle damage in resistance-trained volunteers. References Adams GR, Cheng DC, Haddad F, Baldwin KM: Skeletal muscle hypertrophy in response to isometric, lengthening, and shortening training bouts of equivalent duration. 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CAS PubMed Google Scholar Coombes JS, McNaughton LR: Effects of branched-chain amino acid supplementation on serum creatine kinase and lactate dehydrogenase after prolonged exercise. CAS PubMed Google Scholar Greer BK, Woodard JL, White JP, Arguello EM, Haymes EM: Branched-chain amino acid supplementation and indicators of muscle damage after endurance exercise. CAS PubMed Google Scholar Koba T, Hamada K, Sakurai M, Matsumoto K, Hayase H, Imaizumi K, Tsujimoto H, Mitsuzono R: Branched-chain amino acids supplementation attenuates the accumulation of blood lactate dehydrogenase during distance running. CAS PubMed Google Scholar Nosaka K, Sacco P, Mawatari K: Effects of amino acid supplementation on muscle soreness and damage. CAS PubMed Google Scholar Jackman SR, Witard OC, Jeukendrup AE, Tipton KD: Branched-chain amino acid ingestion can ameliorate soreness from eccentric exercise. Article CAS PubMed Google Scholar Shimomura Y, Inaguma A, Watanabe S, Yamamoto Y, Muramatsu Y, Bajotto G, Sato J, Shimomura N, Kobayashi H, Mawatari K: Branched-chain amino acid supplementation before squat exercise and delayed-onset muscle soreness. CAS PubMed Google Scholar Borsheim E, Cree MG, Tipton KD, Elliott TA, Aarsland A, Wolfe RR: Effect of carbohydrate intake on net muscle protein synthesis during recovery from resistance exercise. Article CAS PubMed Google Scholar Stock MS, Young JC, Golding LA, Kruskall LJ, Tandy RD, Conway-Klaassen JM, Beck TW: The effects of adding leucine to pre and postexercise carbohydrate beverages on acute muscle recovery from resistance training. Article PubMed Google Scholar Sharp CP, Pearson DR: Amino acid supplements and recovery from high-intensity resistance training. Article PubMed Google Scholar van Someren KA, Edwards AJ, Howatson G: Supplementation with beta-hydroxy-beta-methylbutyrate hmb and alpha-ketoisocaproic acid kic reduces signs and symptoms of exercise-induced muscle damage in man. CAS PubMed Google Scholar Blomstrand E, Andersson S, Hassmen P, Ekblom B, Newsholme EA: Effect of branched-chain amino acid and carbohydrate supplementation on the exercise-induced change in plasma and muscle concentration of amino acids in human subjects. Article CAS PubMed Google Scholar Goodall S, Howatson G: The effects of multiple cold water immersions on indices of muscle damage. A previous study reported that BCAA decrease the levels of Th1-derived cytokines interferon-γ and interleukin-2 after high-intensity exercise, including triathlon and long-distance running [ 22 ]. Furthermore, taurine is an important factor in the neutrophil-related inflammatory response because it scavenges hypochlorous acid excreted from activated neutrophils and forms the less toxic taurine-chloramine [ 16 , 17 ]. Consequently, the production of pro-inflammatory mediators, such as prostaglandin E2 PGE2 , nitric oxide, and cytokines, from macrophages and lymphocytes are suppressed [ 34 ]. In particular, PGE2 has been considered a critical inflammatory mediator because it is produced by macrophages, sensitizes muscle afferent nociceptors [ 35 ], and is associated with the production of bradykinin, a substrate known to mediate muscle pain [ 36 ]. However, this hypothesis requires verification. In the present study, the combination of BCAA and taurine suppressed DOMS and the levels of serum marker of oxidative stress. The general consensus is that muscle hypertrophy is induced during the recovery from damages to the microstructure of the muscle fiber and extracellular matrix [ 39 ]. Because exercise-induced symptoms including the production of inflammatory cytokine interleukin-6; IL-6, and fibroblast growth factor-2 , oxidative stress and DOMS usually occur during recovery, these responses have been suggested to be necessary for exercise-induced muscle hypertrophy [ 40 , 41 ]. Therefore, even if DOMS and muscle damage were effectively attenuated by the combination of BCAA and taurine supplementation, there is a possibility that muscle hypertrophy can be also be suppressed, and previous reports have shown that supplementations of taurine or multi-nutrient including BCAA and taurine could attenuate the productions of reactive oxygen species [ 16 ] and IL-6 [ 19 ]. On the other hand, Flann et al. evaluated whether exercise-induced symptoms including muscle soreness and damage are necessary events for muscle remodeling in humans [ 42 ]. They showed that the volume and strength of the quadriceps muscle and the muscular mRNA expression of the myogenic insulin-like growth factor-IEa that contributes to muscle regeneration were caused independently of muscle soreness and increase serum CK levels. Thus, DOMS and inflammation are not always necessary for muscle hypertrophy to occur. Furthermore, if exercise-induced DOMS and inflammation are efficiently attenuated, subjects can avoid unnecessary pain. This study confirmed that a combination of 3. Therefore, combined supplementation with BCAA and taurine may be a useful strategy for attenuating DOMS and muscle damage and can help motivate beginners to continue an exercise program while assisting competitive athletes to train at higher intensity. 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Stock MS, Young JC, Golding LA, Kruskall LJ, Tandy RD, Conway-Klaassen JM, Beck TW: The effects of adding leucine to pre and postexercise carbohydrate beverages on acute muscle recovery from resistance training. J Strength Cond Res. Article PubMed Google Scholar. White JP, Wilson JM, Austin KG, Greer BK, St John N, Panton LB: Effect of carbohydrate-protein supplement timing on acute exercise-induced muscle damage. J Int Soc Sports Nutr. Article PubMed Central PubMed Google Scholar. Schaffer SW, Jong CJ, Ramila KC, Azuma J: Physiological roles of taurine in heart and muscle. J Biomed Sci. Dawson R, Biasetti M, Messina S, Dominy J: The cytoprotective role of taurine in exercise-induced muscle injury. Amino Acids. Silva LA, Silveira PC, Ronsani MM, Souza PS, Scheffer D, Vieira LC, Benetti M, De Souza CT, Pinho RA: Taurine supplementation decreases oxidative stress in skeletal muscle after eccentric exercise. Cell Biochem Funct. Miyazaki T, Karube M, Matsuzaki Y, Ikegami T, Doy M, Tanaka N, Bouscarel B: Taurine inhibits oxidative damage and prevents fibrosis in carbon tetrachloride-induced hepatic fibrosis. J Hepatol. Miyazaki T, Matsuzaki Y, Ikegami T, Miyakawa S, Doy M, Tanaka N, Bouscarel B: Optimal and effective oral dose of taurine to prolong exercise performance in rat. Dunn-Lewis C, Kraemer WJ, Kupchak BR, Kelly NA, Creighton BA, Luk HY, Ballard KD, Comstock BA, Szivak TK, Hooper DR, Denegar CR, Volek JS: A multi-nutrient supplement reduced markers of inflammation and improved physical performance in active individuals of middle to older age: a randomized, double-blind, placebo-controlled study. Nutr J. Yatabe Y, Miyakawa S, Miyazaki T, Matsuzaki Y, Ochiai N: Effects of taurine administration in rat skeletal muscles on exercise. J Orthop Sci. Galloway SD, Talanian JL, Shoveller AK, Heigenhauser GJ, Spriet LL: Seven days of oral taurine supplementation does not increase muscle taurine content or alter substrate metabolism during prolonged exercise in humans. J Appl Physiol. Bassit RA, Sawada LA, Bacurau RF, Navarro F, Martins E, Santos RV, Caperuto EC, Rogeri P, Costa Rosa LF: Branched-chain amino acid supplementation and the immune response of long-distance athletes. Ishikura K, Miyakawa S, Yatabe Y, Takekoshi K, Omori H: Effect of taurine supplementation on blood glucose concentration during prolonged exercise. Jpn J Phys Fitness Sports Med. Article Google Scholar. Shimomura Y, Fujii H, Suzuki M, Murakami T, Fujitsuka N, Nakai N: Branched-chain alpha-keto acid dehydrogenase complex in rat skeletal muscle: regulation of the activity and gene expression by nutrition and physical exercise. Nosaka K, Sacco P, Mawatari K: Effects of amino acid supplementation on muscle soreness and damage. Ishikura K, Miyazaki T, Ra SG, Endo S, Nakamura Y, Matsuzaka T, Miyakawa S, Ohmori H: Effect of taurine supplementation on the alteration in amino acid content in skeletal muscle with exercise in rat. J Sport Sci Med. Google Scholar. Tang FC: Influence of branched-chain amino acid supplementation on urinary protein metabolite concentrations after swimming. J Am Coll Nutr. Hamada K, Koba T, Sakurai M, Matsumoto K, Higuchi T, Imaizumi K, Hayase H, Ueno H: Effective dose of branched-chain amino acids on blood response in healthy men. J Jpn Soc Clin Nutr. Radak Z, Pucsok J, Mecseki S, Csont T, Ferdinandy P: Muscle soreness-induced reduction in force generation is accompanied by increased nitric oxide content and DNA damage in human skeletal muscle. Free Radic Biol Med. Ohno T, Tanaka Y, Sugauchi F, Orito E, Hasegawa I, Nukaya H, Kato A, Matunaga S, Endo M, Tanaka Y, Sakakibara K, Mizokami M: Suppressive effect of oral administration of branched-chain amino acid granules on oxidative stress and inflammation in HCV-positive patients with liver cirrhosis. Hepatol Res. Szymanski DJ: Recommendations for the avoidance of delayed onset muscle soreness. Strength Cond J. Peake J, Nosaka K, Suzuki K: Characterization of inflammatory responses to eccentric exercise in humans. Exerc Immunol Rev. PubMed Google Scholar. Croisier JL, Camus G, Deby-Dupont G, Bertrand F, Lhermerout C, Crielaard JM, Juchmes-Ferir A, Deby C, Albert A, Lamy M: Myocellular enzyme leakage, polymorphonuclear neutrophil activation and delayed onset muscle soreness induced by isokinetic eccentric exercise. Arch Physiol Biochem. Schuller-Levis GB, Park E: Taurine: new implications for an old amino acid. FEMS Microbiol Lett. Cheung K, Hume P, Maxwell L: Delayed onset muscle soreness: treatment strategies and performance factors. Sports Med. Murase S, Terazawa E, Queme F, Ota H, Matsuda T, Hirate K, Kozaki Y, Katanosaka K, Taguchi T, Urai H, Mizumura K: Bradykinin and nerve growth factor play pivotal roles in muscular mechanical hyperalgesia after exercise delayed-onset muscle soreness. J Neurosci. Kudo I, Murakami M: Phospholipase A2 enzymes. Prostaglandins Other Lipid Mediat. Gijon MA, Spencer DM, Siddiqi AR, Bonventre JV, Leslie CC: Cytosolic phospholipase A2 is required for macrophage arachidonic acid release by agonists that Do and Do not mobilize calcium. Novel role of mitogen-activated protein kinase pathways in cytosolic phospholipase A2 regulation. J Biol Chem. Newham DJ, McPhail G, Mills KR, Edwards RH: Ultrastructural changes after concentric and eccentric contractions of human muscle. J Neurol Sci. Olwin BB, Hannon K, Kudla AJ: Are fibroblast growth factors regulators of myogenesis in vivo?. Prog Growth Factor Res. Radak Z, Chung HY, Goto S: Systemic adaptation to oxidative challenge induced by regular exercise. Flann KL, LaStayo PC, McClain DA, Hazel M, Lindstedt SL: Muscle damage and muscle remodeling: no pain, no gain?. J Exp Biol. Download references. This study was supported in part by an educational grant from the Seikatsu Bunkasya Co. Chiba, Japan. The authors would like to thank Dr. Masaharu Ito of Livence Co. Tokyo, Japan , and Noriko Murakami and Norikazu Watanabe of Seikatsu Bunkasya Co. for their helpful discussion and assistance. The authors are also grateful to the Kasumigaura Research Agency for Adult Diseases Ami, Japan for the masked wrapping of amino acid powder for the double-blind study and to the Chemical Analysis Center, University of Tsukuba, for amino acids analysis. This work was presented in part at the 12th International Congress on Amino Acids, Peptides and Proteins in August , and at the 18th International Taurine Meeting in April Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, , Japan. Research Fellow of the Japan Society for the Promotion of Sciences, Chiyoda-ku, Tokyo, , Japan. Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, , Japan. Sports Research and Development Core, University of Tsukuba, Tsukuba, Ibaraki, , Japan. School of Health and Physical Education, University of Tsukuba, Tsukuba, Ibaraki, , Japan. Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, , Japan. Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Ibaraki, , Japan. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, , Japan. You can also search for this author in PubMed Google Scholar. Correspondence to Hajime Ohmori. Significant manuscript writer: SGR, TM, and HO. Concept and design: SGR, TM, SM, YM, and HO. Data acquisition: SGR, TM, KI, HN, and SK. Data analysis and interpretation: SGR, TM, KI, HN, SK, YN, and HO. Statistical expertise: YN. All authors read and approved the final manuscript. Open Access This article is published under license to BioMed Central Ltd. However, your muscles require all of the essential amino acids for the best results. This soreness is called delayed onset muscle soreness DOMS , which develops 12 to 24 hours after exercise and can last up to 72 hours 7. Meanwhile, other research suggests that it may actually be related to the connective tissue associated with the muscle rather than the actual muscle itself 8. BCAAs have been shown to decrease muscle damage, which may help reduce the length and severity of DOMS. Several studies show that BCAAs decrease protein breakdown during exercise and decrease levels of creatine kinase, which is an indicator of muscle damage 9 , In one study, people who supplemented with BCAAs before a squat exercise experienced reduced DOMS and muscle fatigue compared to the placebo group Therefore, supplementing with BCAAs, especially before exercise, may speed up recovery time Just as BCAAs may help decrease muscle soreness from exercise, they may also help reduce exercise-induced fatigue. Everyone experiences fatigue and exhaustion from exercise at some point. How quickly you tire depends on several factors, including exercise intensity and duration, environmental conditions, and your nutrition and fitness level Your muscles use BCAAs during exercise, causing levels in your blood to decrease. When blood levels of BCAAs decline, levels of the essential amino acid tryptophan in your brain increase In your brain, tryptophan is converted to serotonin , a brain chemical that is thought to contribute to the development of fatigue during exercise 14 , In two studies, participants who supplemented with BCAAs experienced a reduction in central fatigue, resulting in improved athletic performance 16 , BCAAs can alter levels of certain chemicals in the brain, such as serotonin, which may be useful in decreasing exercise-induced fatigue. Muscle proteins are constantly broken down and rebuilt synthesized. The balance between muscle protein breakdown and synthesis determines the amount of protein in muscle Muscle wasting is a sign of malnutrition and occurs with chronic infections, cancer, periods of fasting , and as a natural part of the aging process 19 , Several studies support the use of BCAA supplements for inhibiting muscle protein breakdown. This may improve health outcomes and quality of living in certain populations, such as older adults and those with conditions like cancer 23 , Taking BCAA supplements can prevent the breakdown of protein in certain populations with muscle wasting. BCAAs may offer health benefits for people with cirrhosis, a chronic disease in which the liver does not function properly. While certain sugars and antibiotics are the mainstays of treatment for hepatic encephalopathy, BCAAs may also benefit people with this condition One review of 16 studies including people with hepatic encephalopathy found that taking BCAA supplements had a beneficial effect on the symptoms and signs of the disease, but had no effect on mortality Liver cirrhosis is also a major risk factor for the development of hepatocellular carcinoma, the most common form of liver cancer, for which BCAA supplements may also be useful 28 , 29 , Several older studies have shown that taking BCAA supplements may offer protection against liver cancer in people with liver cirrhosis 31 , As such, scientific authorities recommend these supplements as a nutritional intervention for liver disease to prevent complications BCAA supplements may improve the health outcomes of people with liver disease, while also possibly protecting against liver cancer. BCAAs are found in foods and whole protein supplements. Getting BCAAs from complete protein sources is more beneficial, as they contain all the essential amino acids. Fortunately, BCAAs are available in a variety of food sources. This makes BCAA supplements unnecessary for most, especially if you consume enough protein in your diet already Consuming protein-rich foods will also provide you with other important nutrients that BCAA supplements lack. |
| Background | About this article Cite muacle article Ra, SG. How we reviewed this Heart health awareness History. Consecutive-day Glucometer test supplies performance. BCAA supplementation damsge improved energy metabolism and lowered levels of dakage BCAA and muscle damage prevention indicate muscle damage, such as creatine kinase and lactate dehydrogenase. To avoid daily variations in the measurement position, these sites on the upper arm were marked with a semi-permanent ink pen during the first testing session. The body uses amino acids to make proteins, which are the building blocks of every cell, tissue, and organ. |
BCAA and muscle damage prevention -
The researchers found that the participants who took BCAAs had a more significant decrease in body fat and a greater increase in lean mass, compared with the other groups. According to a review , a variety of illnesses can affect protein synthesis, which can lead to a loss of body protein and skeletal muscle mass.
The authors found evidence that a high-protein diet that provides additional leucine can help maintain muscle mass in people with chronic diseases such as cancer.
A systematic review found some evidence that BCAA supplementation can help reduce the muscle damage that occurs during high-intensity exercise.
However, the authors caution that the evidence base was limited to one small study and that confirming these findings will require more research. Results of a small study from show that adult male participants who took a BCAA supplement during exercise had lower blood levels of substances that indicate muscle damage than those who took a placebo.
The researchers concluded that BCAA supplementation may reduce muscle damage after endurance exercises. A study investigated the effects of combined BCAA and arginine supplementation on intermittent sprint performance over 2 consecutive days. Arginine is another type of amino acid.
The study involved 7 females and 15 males who had competed at a national or international level in handball. The participants played simulated handball games over 2 consecutive days. The researchers found that intermittent sprint performance on the second day was significantly better in the athletes who had taken the supplement, compared with those who had taken the placebo.
In a study , researchers randomly assigned participants with advanced liver cirrhosis into groups. For at least 6 months, each group consumed either BCAAs daily or a diet without BCAAs. Over 2 years, Model for End-Stage Liver Disease MELD test scores improved significantly among participants who consumed BCAAs, compared with those who did not.
Doctors calculate MELD scores by measuring levels of certain substances in the blood, such as creatinine and bilirubin. They use the resulting score to help determine how close a person is to having liver failure. The authors concluded that long-term BCAA supplementation has beneficial effects in people with advanced liver cirrhosis and that understanding these effects will require further research.
Another study from also found that BCCA supplementation improved low muscle strength among people with liver cirrhosis. BCAAs are essential amino acids, which means that the body cannot make them.
However, a wide variety of foods contain BCAAs, and most people can get enough by eating a protein-rich diet. Also, many health and fitness stores sell BCAA supplements, and a person can purchase them online.
There is no officially recommended BCAA dosage. Depending on the desired benefit, studies have used different dosages of these supplements. However, anyone who experiences serious side effects should stop taking the supplement and consult their doctor.
BCAAs are essential amino acids. The body cannot make them, so a person needs to get BCAAs from their diet or as supplements. Research suggests that taking BCAA supplements may improve muscle mass and performance and may reduce muscle damage from exercise.
BCAAs may also benefit people with liver disease. However, some research links increased BCAA levels to conditions such as diabetes , cancer, liver disease, and heart disease. People can use protein powder to supplement their protein intake, help build muscle, aid muscle recovery, and encourage healthy weight loss.
In this…. What is whey protein? Can it help a person to build muscle, lower cholesterol, or burn fat? Researchers continue to discover potentially therapeutic…. There is evidence that some beneficial muscle-building supplements include protein, creatine, and caffeine.
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Medical News Today. Health Conditions Health Products Discover Tools Connect. Health benefits of BCAAs. Medically reviewed by Alan Carter, Pharm. Exercise performance Lean muscle mass During illness Muscle damage Sprint performance Liver disease Sources Dosage Side effects and risks Summary Supplements containing branched-chain amino acids BCAAs are popular for boosting muscle growth and performance.
Exercise performance. Share on Pinterest BCAA supplements may help improve exercise performance. Lean muscle mass. The repair of EIMD mainly relies on muscle stem cells, termed satellite cells SCs.
After skeletal muscle damage, SCs proliferate and differentiate by expressing sequential transcription factors, such as Paired box7 Pax7 , Myogenic factor 5 Myf5 , Myoblast determination protein MYOD , and Myogenin MYOG Scala et al. Pax7 maintains the quiescent state of SCs.
Myf5 and MYOD mainly regulate SCs proliferation, whereas MYOG controls SCs differentiation Zammit, Understanding the mechanism underlying skeletal muscle repair and finding intervention strategies are important for accelerating the recovery process from EIMD.
Studies suggest the EIMD-induced inflammatory response is an integral part of the repair process Fatouros and Jamurtas, Macrophages, with their inflammatory responses, play an important role in promoting skeletal muscle repair Markus et al.
Generally, macrophages divide into two types: The classically activated M1 macrophages and the alternatively activated M2 macrophages. M1 macrophages are present in the pro-inflammatory period of EIMD and associated with SCs proliferation Otis et al.
Importantly, M1 and M2 macrophages require different metabolic programs to support energy demands. M1 macrophages are mainly dependent on glycolysis metabolism, mediated by HIF1α Wang et al. This suggests that macrophage metabolism and polarization are closely linked, and macrophage polarization may be regulated by metabolic pathways.
Human studies have shown that Branched-Chain Amino Acids BCAAs supplementation is an effective approach to accelerate the recovery from EIMD Rahimi et al. BCAAs, including leucine, isoleucine, and valine, are essential amino acids for mammals.
BCAA, particularly leucine, activates the mammalian target of rapamycin complex 1 mTORC1 , a central signaling node that exerts widespread control over cellular metabolism and growth Wolfson and Sabatini, Mammalian target of rapamycin mTOR plays an important role in the macrophages function by regulating gene expression at the transcriptional and translational levels Kang and Kumanogoh, In recent years, BCAAs have been closely linked with glucose and lipid metabolism in metabolic and cardiovascular diseases Wang et al.
As a nutritional supplement, BCAAs reduce muscle soreness and the level of muscle damage biomarkers Matsumoto et al. However, the underlying mechanism remains to be fully understood.
In this study, we established an EIMD model and explored the role of macrophages in BCAA alleviated skeletal muscle damage. In addition, we further explored the mechanism of BCAA regulated macrophage polarization and the effect of BCAA-intervened macrophages on satellite cells.
Male Sprague—Dawley rats 8-week-old; Charles River Laboratories China, Inc. The protocol was approved by the Animal Research Ethics Committee of Beijing Sport University. On the day of eccentric exercise, BCAA supplement was administered immediately after the exercise.
All animals in the placebo group PLA received distilled water by oral gavage once a day over the same period. For the exercise group, 8 rats from each group were sacrificed at each time point of 1, 3, 5, and 7 days after the eccentric exercise. The gastrocnemius muscle and blood were collected at various time points.
The serum was collected from abdominal aorta of rats at each indicated time. The final signals were read using a pan-wavelength micro plate reader BioTek Instruments, United States.
For immunohistochemical analysis, the sections were adhered to poly-L-lysine-coated slides. Further, the sections were deparaffinized and fixed in 0. Primary peritoneal macrophages M0 were isolated from mice as previously described Bisgaard et al. After 3 days, mouse was euthanized by cervical dislocation.
The peritoneal fluid was collected and centrifuged for 10 min at 1, rpm in a refrigerated centrifuge. The cell pellet was resuspended in DMEM medium and cells were cultured for 4—6 h at 37°C, during which the peritoneal macrophages attached to culture plates, allowing their separation from other types of cells.
Subsequently, non-adherent cells were removed by gently washing 3 times with warm PBS. M1 and M2 macrophages were obtained by incubating with LPS 0.
Macrophages were treated with different concentrations of BCAAs as previously described Lian et al. Cells were treated with 2-deoxy-D-glucose Liu et al.
M0 macrophages were stimulated with LPS or IL-4 in the presence or absence of BCAAs in culture medium for 24 h, respectively. C2C12 cells proliferation was assessed by Cell Counting Kit-8 CCK8, Dojindo, Japan.
The measurement was done using a pan-wavelength micro plate reader BioTek Instruments, United States at nm. The total RNA were extracted from cells using Trizol reagent Invitrogen, United States and reverse transcribed into cDNA using RT SuperMix kit Promega, United States.
Real-time quantitative PCR q-PCR was performed using SYBR Green PCR mix ABI, United States and real-time PCR system Bio-Rad with the primer sequences in Table 1. All values are expressed as mean ± SEM. To explore the effect of BCAAs on EIMD, we established a rat model with EIMD, and treated the rats with or without BCAAs.
The muscle fibers of the gastrocnemius in the PLA group showed varying degrees of swelling and dilated intercellular space after EIMD Figures 1A,B. Moreover, the serum CK levels were increased after EIMD Figure 1C. These changes indicated that the EIMD model was successfully constructed.
Importantly, with BCAA treatment, the muscle fiber swelling was decreased on the first day after EIMD Figure 1B and the serum CK level was lower at the fifth and seventh day after EIMD Figure 1C , compared with those in the PLA group.
Meanwhile, the expression of SCs proliferation marker MYOD was increased in BCAA group Figure 1D. In addition, BCAA advanced the peak expression of another SCs differentiation marker MYOG by 2 days, indicating that BCAA supplementation accelerated the repair of EIMD Figure 1E.
Collectively, these data demonstrated that BCAA supplementation promoted EIMD repair, consistent with previous studies Kato et al. FIGURE 1. Branched-chain amino acids BCAAs promote the repair of exercise-induced muscle damage EIMD. B The effect of BCAAs on the cross-sectional area of gastrocnemius fibers in rats with EIMD.
C The effect of BCAAs on serum CK levels in rats with EIMD. D,E The effect of BCAAs on the proliferation MYOD and differentiation MYOG of the gastrocnemius satellite cells SCs in rats with EIMD.
Data are presented as mean ± SEM. Immunohistochemical results revealed that BCAAs enhanced the protein expression of CD68 M1 and CD M2 during EIMD repair Figures 2A—D. BCAA advanced the peak expression of CD68 by 2 days, suggesting that BCAAs accelerated macrophages M1 polarization during EIMD repair.
Meanwhile, BCAAs increased the serum levels of proinflammatory cytokine IL-6 in the early stage of EIMD repair Figure 2E and the serum levels of anti-inflammatory cytokines IL in the late stage Figure 2F. Collectively, these data suggested that BCAAs promoted both M1 and M2 polarization of macrophages during EIMD repair.
FIGURE 2. BCAAs promote M1 and M2 polarization of macrophages during EIMD repair. E,F The effects of BCAAs on serum levels of inflammatory cytokines, namely, IL-6, and IL during EIMD repair. We analyzed the direct effects of BCAAs on the polarization of M1 macrophages in vitro.
We isolated the primary peritoneal macrophages from mice and exposed them to LPS with or without BCAAs in culture medium. FIGURE 3. BCAA-promoted M1 macrophages enhance the proliferation of SCs. A—C The effects of various concentrations of BCAAs on the polarization of M1 macrophages.
D,E The effect of BCAA μm -treated M1 macrophages on C2C12 proliferation. It has been suggested that M1 macrophage affects SCs proliferation Minari and Thomatieli-Santos, We then tested whether the conditioned medium from M1 macrophages treated with BCAA could enhance SCs proliferation.
To do so, M0 macrophages were prestimulated with LPS with or without BCAA for 24 h. Fresh medium was then added to the M1 macrophages for 12 h and collected as conditioned media. C2C12 cells were then cultured with these conditioned media for 24 or 48 h.
As expected, medium from M1 macrophages promoted the mRNA expression of Myf5, which is further enhanced by BCAA-promoted M1 macrophages Figure 3D.
Further, we analyzed the proliferation of C2C12 cells cultured with conditioned medium using the CCK8 kit. The result showed that the conditioned medium from prestimulated M1 macrophages promoted C2C12 cells growth, which was further enhanced by the conditioned medium from BCAA-treated M1 macrophages Figure 3E.
Collectively, these data suggested that BCAA-promoted M1 macrophages could enhance the proliferation of SCs. We also explored the direct effects of BCAAs on the polarization of M2 macrophages in vitro. The primary peritoneal macrophages were isolated from mice and exposed to IL-4 with or without BCAAs in culture medium.
FIGURE 4. BCAA-promoted M2 macrophages enhance the differentiation of SCs. A—C The effect of BCAAs μm on M2 polarization of macrophages. D,E The effect of BCAA μm -treated M2 macrophages on C2C12 differentiation. It has been suggested that M2 affects SC differentiation Minari and Thomatieli-Santos, We then tested whether the conditioned medium from BCAA-promoted M2 macrophages could affect SCs differentiation.
C2C12 cells were cultured with differentiation medium and conditioned media from M2 or BCAA-treated M2 for 24 or 48 h. As expected, the conditioned medium from M2 macrophages promoted the mRNA expression of MYOG and myosin heavy chain 4 Myh4 in C2C12 cells, which was further enhanced by the conditioned medium from BCAA-promoted M2 macrophages Figures 4D,E.
Collectively, these data indicated that BCAA-promoted M2 macrophages enhanced the differentiation of SCs. Next, we investigated how BCAA promoted M1 polarization. M1 macrophages are essentially glycolytic cells Juban and Chazaud, mTORC1 is a central regulator of cellular metabolism, including glycolysis, and can be activated by BCAA.
We then investigated the role of mTORC1 in the BCAA-promoted M1 polarization. As expected, BCAAs enhanced the activity of mTORC1 in the process of M1 polarization Figures 5A—C.
FIGURE 5. BCAAs promote M1 polarization via mTORC1-HIF1α-glycolysis pathway. A—C BCAAs μm promoted the expression of HIF1α and mTORC1 activation during M1 polarization, and the effect of RAPA rapamycin, mTORC1 inhibitor on the expression of HIF1α.
D—F Changes of M1 polarization with RAPA. G—I The effect of RAPA on the rate-limiting enzyme of glycolysis. J,K Changes of M1 polarization with 2-DG, a glycolysis inhibitor.
Hypoxia-inducible factor 1α HIF1α , a transcriptional factor targeted by mTORC1, controls glycolysis and M1 polarization Wang et al. BCAAs increased the protein level of HIF1α during M1 polarization Figures 5B,C.
Rapamycin abolished the BCAA-induced HIF1α and glycolytic enzymes expression HK2, PFK1 and LDHA Figures 5B,G—I. Furthermore, 2-DG, the inhibitor of glycolysis, attenuated the mRNA levels of TNF-α and iNOS induced by BCAA Figures 5J,K , suggesting a weakened M1 polarization.
Collectively, these data demonstrated that BCAAs promoted M1 polarization via activating the mTORC1-HIF1α-glycolysis pathway. We also explored how BCAA promoted M2 polarization. Lipid metabolic reprogramming is essential for M2 polarization van den Bosch et al.
mTORC1 and its downstream transcription factor PPARγ are key regulators of lipid metabolism in M2 polarization. We then investigated the role of mTORC1 and PPARγ in the BCAA-promoted M2 polarization.
As expected, BCAAs enhanced the activity of mTORC1 and the protein level of PPARγ during M2 polarization Figures 6A,B. Interestingly, rapamycin abolished the BCAA-induced mTORC1 activation and PPARγ expression Figure 6C , but showed no effect on BCAA-promoted M2 polarization Figures 6D—F.
Collectively, these data suggested that BCAAs promoted M2 polarization independent of the mTORC1-PPARγ pathway.
FIGURE 6. BCAAs promote M2 polarization independent of the mTORC1-PPARγ pathway. A—C BCAAs μm enhanced the expression of PPARγ and mTORC1 activity during M2 polarization, and the effect of RAPA rapamycin, mTORC1 inhibitor on the expression of PPARγ.
D—F The effect of RAPA on the change in M2 polarization. Data are expressed as mean ± SEM. In the present study, we demonstrated BCAA supplementation promotes the repair of EIMD via enhancing macrophage polarization.
M1 and M2 macrophages stimulate the proliferation and differentiation of muscle satellite cells, respectively. Previous studies have shown that BCAA supplementation alleviate the level of CK and muscle soreness following EIMD in human.
In the present study, our results also indicated that BCAA supplementation reduce the level of CK and accelerate the recovery of damaged muscle fibers, which is consistent with previous studies Fouré and Bendahan, ; Doma et al.
Kato et al. This phenomenon suggested that BCAA-improved EIMD may be related to inflammation. Previous studies indicated that macrophages play an important role during skeletal muscle repair Juhas et al.
There is no relevant study on whether BCAA intervention affect macrophage polarization during EIMD. Our results showed that BCAA enhances M1 and M2 polarization during skeletal muscle repair in different time stages, meanwhile, similar changes in the serum levels of inflammatory factors were observed in vitro.
These data suggested that macrophage polarization plays an important role in BCAA-induced muscle repair. In addition, skeletal muscle repair is a complex biological process, the activation, proliferation, and differentiation of SCs provides the potential capacity to muscle repair La et al.
In the current study, our results showed that BCAA supplementation promotes the proliferation and differentiation of skeletal muscle SCs, which is consistent with previous study Duan et al.
However, Kato et al. This discrepancy could be attributed to the different muscle damage models. Further experiments are warranted to analyze the differences between these two muscle damage models.
Our results show BCAAs promote M1 and M2 polarization of macrophages, which further promote the proliferation and differentiation of SCs, respectively.
Previous studies have reported that the pro-inflammatory and anti-inflammatory factors promote the proliferation and differentiation of SCs, respectively Akahori et al. It can be speculated that BCAA-promoted pro- and anti-inflammatory factors mediate the stimulation of SC proliferation and differentiation from M1 and M2 macrophages.
Meanwhile, other possible mechanisms should also be considered. The repair process of skeletal muscle involves a variety of cell types, such as macrophages and SCs Tidball, It is not entirely clear how macrophages and SCs work together to promote skeletal muscle repair.
Shang et al. Due to the important relationship between BCAA and glutamine, we speculate that glutamine may play an important role in BCAA-promoted macrophages stimulating SCs and muscle repair. mTOR signaling pathway is an important link between immune response and cell metabolism, moreover, mTORC1 is an important factor in sensing intracellular amino acid concentration Kang and Kumanogoh, Previous studies show that mTORC1 plays an inconsistent role in M2 polarization.
One study indicates that IL-4 stimulated bone marrow-derived macrophages BMDM from TSC1 knockout mice, which increased mTORC1 activity, M2 polarization weakened Byles et al. However, two other studies showed IL-4 stimulated BMDM with mTOR inhibition Torin1 or Raptor knockout mice decreased mTORC1 activity , M2 polarization weakened Covarrubias et al.
The reasons may be related to different the knockout mice model. In addition, Covarrubias et al. This phenomenon suggests the metabolism in M2 polarization is not only lipid metabolism and may also involve glycolysis. Therefore, further experiments are warranted to explore the mechanism how BCAA regulates M2 polarization.
It has been shown that there is a wide spectrum of macrophage activation states in vivo Murray et al. An expanded range of stimuli can drive macrophage activation with distinct activation profiles in different directions Kang and Kumanogoh, In the current study, we used chemically activated macrophages to investigate the effect of BCAA on macrophage polarization in vitro.
The results of cultured cells were consistent with the expression of macrophage activation markers in vivo.
Whether the macrophage polarization in vitro accurately recapitulates the changes of macrophages in vivo remains to be fully determined. Staining of different types of macrophages in the damaged muscle may be of help. The current study demonstrated that BCAAs promoted C2C12 proliferation and differentiation via enhancing the macrophage polarization in vitro.
On the other hand, when BCAAs intake was increased in vivo , the SCs were exposed to a large number of factors, including the elevated BCAAs and inflammatory factors.
Whether BCAAs exert direct impacts on myoblasts remains to be investigated. It is also possible that there are additive impacts from elevated BCAAs and inflammatory factors.
Nevertheless, our data show that macrophages mediate, at least partially, the impacts of BCAAs on SCs and thus the repair of EIMD. One limitation of our study is that, although we demonstrate that BCAAs promote the function of SCs via macrophages in cultured cells, direct evidence for this occurring in vivo is lacking, which could be provided by macrophage depletion animal model and the staining for SCs to assess their numbers in the damaged muscle.
In summary, the current study shows that BCAAs improve EIMD repair by promoting the proliferation and differentiation of muscle SCs through macrophage polarization. The results highlight the critical role of macrophage in BCAA-induced repair of EIMD and indicate new approaches for the treatment of muscle-related diseases.
Heart health awareness show that BCAAs musfle increase muscle growth, reduce soreness and fatigue, prevent Martial arts lean muscle mass wasting, and umscle liver health. They are BAA found in a ;revention of BCAA and muscle damage prevention sources, including musccle, eggs, and dairy products. There are 20 different amino acids that make up the thousands of different proteins in the human body. Nine of the 20 are considered essential amino acidsmeaning they cannot be made by your body and must be obtained through your diet. Of the nine essential amino acids, three are considered branched-chain amino acids BCAAs : leucineisoleucine, and valine.
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