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      Ergogenic Effect of BCAAs and L-Alanine Supplementation: Proof-of-Concept Study in a Murine Model of Physiological Exercise

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          Abstract

          Background: Branched-chain amino acids (BCAAs: leucine, isoleucine, valine) account for 35% of skeletal muscle essential amino acids (AAs). As such, they must be provided in the diet to support peptide synthesis and inhibit protein breakdown. Although substantial evidence has been collected about the potential usefulness of BCAAs in supporting muscle function and structure, dietary supplements containing BCAAs alone may not be effective in controlling muscle protein turnover, due to the rate-limiting bioavailability of other AAs involved in BCAAs metabolism. Methods: We aimed to evaluate the in vivo/ex vivo effects of a 4-week treatment with an oral formulation containing BCAAs alone (2:1:1) on muscle function, structure, and metabolism in a murine model of physiological exercise, which was compared to three modified formulations combining BCAAs with increasing concentrations of L-Alanine (ALA), an AA controlling BCAAs catabolism. Results: A preliminary pharmacokinetic study confirmed the ability of ALA to boost up BCAAs bioavailability. After 4 weeks, mix 2 (BCAAs + 2ALA) had the best protective effect on mice force and fatigability, as well as on muscle morphology and metabolic indices. Conclusion: Our study corroborates the use of BCAAs + ALA to support muscle health during physiological exercise, underlining how the relative BCAAs/ALA ratio is important to control BCAAs distribution.

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          Most cited references45

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          Interleukin‐6 myokine signaling in skeletal muscle: a double‐edged sword?

          Interleukin (IL)‐6 is a cytokine with pleiotropic functions in different tissues and organs. Skeletal muscle produces and releases significant levels of IL‐6 after prolonged exercise and is therefore considered as a myokine. Muscle is also an important target of the cytokine. IL‐6 signaling has been associated with stimulation of hypertrophic muscle growth and myogenesis through regulation of the proliferative capacity of muscle stem cells. Additional beneficial effects of IL‐6 include regulation of energy metabolism, which is related to the capacity of actively contracting muscle to synthesize and release IL‐6. Paradoxically, deleterious actions for IL‐6 have also been proposed, such as promotion of atrophy and muscle wasting. We review the current evidence for these apparently contradictory effects, the mechanisms involved and discuss their possible biological implications.
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            Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements

            Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are essential amino acids with protein anabolic properties, which have been studied in a number of muscle wasting disorders for more than 50 years. However, until today, there is no consensus regarding their therapeutic effectiveness. In the article is demonstrated that the crucial roles in BCAA metabolism play: (i) skeletal muscle as the initial site of BCAA catabolism accompanied with the release of alanine and glutamine to the blood; (ii) activity of branched-chain keto acid dehydrogenase (BCKD); and (iii) amination of branched-chain keto acids (BCKAs) to BCAAs. Enhanced consumption of BCAA for ammonia detoxification to glutamine in muscles is the cause of decreased BCAA levels in liver cirrhosis and urea cycle disorders. Increased BCKD activity is responsible for enhanced oxidation of BCAA in chronic renal failure, trauma, burn, sepsis, cancer, phenylbutyrate-treated subjects, and during exercise. Decreased BCKD activity is the main cause of increased BCAA levels and BCKAs in maple syrup urine disease, and plays a role in increased BCAA levels in diabetes type 2 and obesity. Increased BCAA concentrations during brief starvation and type 1 diabetes are explained by amination of BCKAs in visceral tissues and decreased uptake of BCAA by muscles. The studies indicate beneficial effects of BCAAs and BCKAs in therapy of chronic renal failure. New therapeutic strategies should be developed to enhance effectiveness and avoid adverse effects of BCAA on ammonia production in subjects with liver cirrhosis and urea cycle disorders. Further studies are needed to elucidate the effects of BCAA supplementation in burn, trauma, sepsis, cancer and exercise. Whether increased BCAA levels only markers are or also contribute to insulin resistance should be known before the decision is taken regarding their suitability in obese subjects and patients with type 2 diabetes. It is concluded that alterations in BCAA metabolism have been found common in a number of disease states and careful studies are needed to elucidate their therapeutic effectiveness in most indications.
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              Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice.

              Recent evidence points to a strong relationship between increased mitochondrial biogenesis and increased survival in eukaryotes. Branched-chain amino acids (BCAAs) have been shown to extend chronological life span in yeast. However, the role of these amino acids in mitochondrial biogenesis and longevity in mammals is unknown. Here, we show that a BCAA-enriched mixture (BCAAem) increased the average life span of mice. BCAAem supplementation increased mitochondrial biogenesis and sirtuin 1 expression in primary cardiac and skeletal myocytes and in cardiac and skeletal muscle, but not in adipose tissue and liver of middle-aged mice, and this was accompanied by enhanced physical endurance. Moreover, the reactive oxygen species (ROS) defense system genes were upregulated, and ROS production was reduced by BCAAem supplementation. All of the BCAAem-mediated effects were strongly attenuated in endothelial nitric oxide synthase null mutant mice. These data reveal an important antiaging role of BCAAs mediated by mitochondrial biogenesis in mammals. Copyright © 2010 Elsevier Inc. All rights reserved.

                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                30 July 2020
                August 2020
                : 12
                : 8
                : 2295
                Affiliations
                [1 ]Section of Pharmacology, Department of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”, Orabona 4—Campus, 70125 Bari, Italy; paola.mantuano@ 123456uniba.it (P.M.); ornella.cappellari@ 123456uniba.it (O.C.); brigida.boccanegra@ 123456uniba.it (B.B.); elena.conte@ 123456uniba.it (E.C.); francesca.sanarica@ 123456uniba.it (F.S.); antonietta.mele@ 123456uniba.it (A.M.); giuliamaria.camerino@ 123456uniba.it (G.M.C.); michela.debellis@ 123456uniba.it (M.D.B.)
                [2 ]Research & Early Development, Dompé farmaceutici S.p.A., Via Campo di Pile, s.n.c., 67100 L’Aquila, Italy; gianluca.bianchini@ 123456dompe.com (G.B.); laura.brandolini@ 123456dompe.com (L.B.); marcello.allegretti@ 123456dompe.com (M.A.)
                Author notes
                [* ]Correspondence: andrea.aramini@ 123456dompe.com (A.A.); annamaria.deluca@ 123456uniba.it (A.D.L.); Tel.: +39-0862-338340 (A.A.); +39-080-5442245 (A.D.L.)
                [†]

                These two authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-6339-2222
                https://orcid.org/0000-0002-1078-8490
                https://orcid.org/0000-0002-5652-7341
                Article
                nutrients-12-02295
                10.3390/nu12082295
                7468919
                32751732
                c24f521f-a000-4160-a1a9-bedc4b5c2e19
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 24 June 2020
                : 27 July 2020
                Categories
                Article

                Nutrition & Dietetics
                dietary supplements,branched-chain amino acids,l-alanine,exercise,resistance to fatigue,preclinical study,murine model

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