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Life without carnosine: development and characterization of a KO rat model for studying the physiological role of carnosine and its implications to physical exercise and muscle metabolism

Abstract

Carnosine (ß-alanyl-L-histidine) is a dipeptide abundantly found in skeletal and cardiac muscles as well as in excitable tissues, although the physiological roles played by carnosine and its methylated analogues are still poorly understood. Evidence indicates that carnosine acts as a physico-chemical buffer during intense efforts, which is corroborated by the performance improvements observed following ²-alanine supplementation. Alternatively, carnosine has been suggested to improve the calcium sensitivity to the contractile apparatus and to protect cellular structures from oxidative damage. In this project, we propose to develop a new knockout rat model with a non-functional CARNS1 gene, leading to the complete absence of carnosine/anserine in their tissues. A successful model is critical to the subsequent aims of the proposed programme of work, which is to investigate the physiological roles of carnosine/anserine and their relevance to exercise and training responses. The knockout rats will be outsourced from an external company and the colony will be established at our Institution, allowing a completely new research line in our University, initially comprising 5 distinct and novel studies that have the potential to answer fundamental questions in this research área but also to hypothesis generate for future reserach programmes. Our initial 5 studies are designed to provide the answers to key fundamental questions that underpin the potential physiological roles of carnosine: 1) to evaluate the impact of carnosine/anserine absence on isolated skeletal muscle contractile proteins, morphology, buffering capacity, expression of genes involved in carnosine metabolism, expression and phosphorylation of calcium-handling proteins and the physiological responses to contraction until exhaustion; 2) to evaluate the impact of carnosine/anserine absence on tolerance to high-intensity exercise, as well as on muscle metabolic responses to exercise, with measures including blood pH and lactate, muscle pH and lactate, muscle glycogen and activity of energy-metabolism key-enzymes; 3) to evaluate the impact of carnosine/anserine absence on total non-enzymatic anti-oxidant capacity of the skeletal muscle and the protection to oxidative damage induced by high-volume aerobic training, with measures including advanced glycation products, markers of cellular damage and protein-bound carbonyl groups; 4) to evaluate the impact of carnosine/anserine absence on left ventricle contractile function (assessed in-vivo and ex-vivo) and miocardial contractile properties (assessed in-vitro), with parallel measures of the calcium transient; 5) to evaluate whether/not carnosine supplementation is able to replenish muscle carnosine content and whether/not this is accompanied by a regain of function, assessing the same functional parameters described above for skeletal and cardiac muscles. In all studies, a group of knockout rats will be compared with a group of age- and body mass-matched wild-type controls. (AU)

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Scientific publications (26)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DOLAN, EIMEAR; SWINTON, PAUL A.; PAINELLI, VITOR DE SALLES; HEMINGWAY, BENEDICT STEPHENS; MAZZOLANI, BRUNA; SMAIRA, FABIANA INFANTE; SAUNDERS, BRYAN; ARTIOLI, GUILHERME G.; GUALANO, BRUNO. A Systematic Risk Assessment and Meta-Analysis on the Use of Oral beta-Alanine Supplementation. ADVANCES IN NUTRITION, v. 10, n. 3, p. 452-463, . (16/50438-0, 13/04806-0, 17/04973-4, 13/14746-4, 15/11328-2, 14/11948-8, 17/09635-0)
OLIVEIRA, L. F.; DE SALLES PAINELLI, V.; NEMEZIO, K.; GONCALVES, L. S.; YAMAGUCHI, G.; SAUNDERS, B.; GUALANO, B.; ARTIOLI, G. G.. Chronic lactate supplementation does not improve blood buffering capacity and repeated high-intensity exercise. SCANDINAVIAN JOURNAL OF MEDICINE & SCIENCE IN SPORTS, v. 27, n. 11, p. 1231-1239, . (13/04806-0, 14/11948-8, 13/14746-4)
SAUNDERS, BRYAN; PAINELLI, VITOR DE SALLES; DE OLIVEIRA, LUANA FARIAS; SILVA, VINICIUS DA EIRA; DA SILVA, RAFAEL PIRES; RIANI, LUIZ; FRANCHI, MARIANA; GONCALVES, LIVIA DE SOUZA; HARRIS, ROGER CHARLES; ROSCHEL, HAMILTON; et al. Twenty-four Weeks of beta-Alanine Supplementation on Carnosine Content, Related Genes, and Exercise. MEDICINE AND SCIENCE IN SPORTS AND EXERCISE, v. 49, n. 5, p. 896-906, . (13/14746-4, 14/11948-8, 12/13026-5, 11/19513-2, 13/04806-0, 15/22686-7)
DE ARAUJO DIAS, GABRIELA FROIO; SILVA, VINICIUS DA EIRA; PAINELLI, VITOR DE SALLES; SALE, CRAIG; ARTIOLI, GUILHERME GIANNINI; GUALANO, BRUNO; SAUNDERS, BRYAN. (In) Consistencies in Responses to Sodium Bicarbonate Supplementation: A Randomised, Repeated Measures, Counterbalanced and Double-Blind Study. PLoS One, v. 10, n. 11, . (13/04806-0, 11/19513-2, 14/11948-8, 13/14746-4)
MATTHEWS, JOSEPH J.; ARTIOLI, GUILHERME G.; TURNER, MARK D.; SALE, CRAIG. The Physiological Roles of Carnosine and beta-Alanine in Exercising Human Skeletal Muscle. MEDICINE AND SCIENCE IN SPORTS AND EXERCISE, v. 51, n. 10, p. 2098-2108, . (14/11948-8)
REZENDE, NATHALIA SAFFIOTI; SWINTON, PAUL; DE OLIVEIRA, LUANA FARIAS; DA SILVA, RAFAEL PIRES; DA EIRA SILVA, VINICIUS; NEMEZIO, KLEINER; YAMAGUCHI, GUILHERME; ARTIOLI, GUILHERME GIANNINI; GUALANO, BRUNO; SAUNDERS, BRYAN; et al. The Muscle Carnosine Response to Beta-Alanine Supplementation: A Systematic Review With Bayesian Individual and Aggregate Data E-Max Model and Meta-Analysis. FRONTIERS IN PHYSIOLOGY, v. 11, . (19/05616-6, 19/27758-7, 17/23688-9, 17/04973-4, 15/23176-2, 13/14746-4, 14/11948-8, 17/09635-0)
GONCALVES, LIVIA DE SOUZA; FRANCHI, MARIANA; MATHOR, MONICA B.; LUGAO, ADEMAR B.; CARVALHO, VICTOR H.; MEDEIROS, MARISA H. G.; ARTIOLI, GUILHERME GIANNINI; VARCA, GUSTAVO H. C.. The molecular structure of beta-alanine is resistant to sterilising doses of gamma radiation. PLoS One, v. 14, n. 1, . (14/11948-8, 13/07937-8, 15/13979-0, 15/22686-7)
YAMAGUCHI, GUILHERME CARVALHO; NEMEZIO, KLEINER; SCHULZ, MARIANE LEICHSENRING; NATALI, JOSE; CESAR, JONATAS EDUARDO; RIANI, LUIZ AUGUSTO; GONCALVES, LIVIA DE SOUZA; MOLLER, GABRIELLA BERWIG; SALE, CRAIG; GENNARI DE MEDEIROS, MARISA HELENA; et al. Kinetics of Muscle Carnosine Decay after beta-Alanine Supplementation: A 16-wk Washout Study. MEDICINE AND SCIENCE IN SPORTS AND EXERCISE, v. 53, n. 5, p. 1079-1088, . (13/07937-8, 17/13552-2, 19/25032-9, 14/11948-8, 13/14746-4)
MATTHEWS, JOSEPH J.; DOLAN, EIMEAR; SWINTON, PAUL A.; SANTOS, LIVIA; ARTIOLI, GUILHERME G.; TURNER, MARK D.; ELLIOTT-SALE, KIRSTY J.; SALE, CRAIG. The effect of carnosine or beta-alanine supplementation on markers of glycaemic control and insulin resistance in human and animal studies: a protocol for a systematic review and meta-analysis. SYSTEMATIC REVIEWS, v. 9, n. 1, . (14/11948-8, 19/26899-6, 19/25032-9, 19/05616-6)
MATTHEWS, JOSEPH J.; DOLAN, EIMEAR; SWINTON, PAUL A.; SANTOS, LIVIA; ARTIOLI, GUILHERME G.; TURNER, MARK D.; ELLIOTT-SALE, KIRSTY J.; SALE, CRAIG. Effect of Carnosine or beta-Alanine Supplementation on Markers of Glycemic Control and Insulin Resistance in Humans and Animals: A Systematic Review and Meta-analysis. ADVANCES IN NUTRITION, v. 12, n. 6, p. 2216-2231, . (19/05616-6, 19/26899-6, 14/11948-8, 19/25032-9)
SAUNDERS, BRYAN; FRANCHI, MARIANA; DE OLIVEIRA, LUANA FARIAS; SILVA, VINICIUS DA EIRA; DA SILVA, RAFAEL PIRES; PAINELLI, VITOR DE SALLES; RIANI COSTA, LUIZ AUGUSTO; SALE, CRAIG; HARRIS, ROGER CHARLES; ROSCHEL, HAMILTON; et al. 24-Week beta-alanine ingestion does not affect muscle taurine or clinical blood parameters in healthy males. EUROPEAN JOURNAL OF NUTRITION, v. 59, n. 1, p. 57-65, . (16/50438-0, 12/13026-5, 13/04806-0, 17/04973-4, 15/22686-7, 13/14746-4, 14/11948-8)
JONES, REBECCA L.; STELLINGWERFF, TRENT; SWINTON, PAUL; ARTIOLI, GUILHERME GIANNINI; SAUNDERS, BRYAN; SALE, CRAIG. Warm-Up Intensity Does Not Affect the Ergogenic Effect of Sodium Bicarbonate in Adult Men. INTERNATIONAL JOURNAL OF SPORT NUTRITION AND EXERCISE METABOLISM, v. 31, n. 6, p. 482-489, . (19/25032-9, 14/11948-8, 16/50438-0)
NEMEZIO, KLEINER; YAMAGUCHI, GUILHERME DE CARVALHO; BOITO RAMKRAPES, ANA PAULA; SCHULZ, MARIANE LEICHSENRING; BAPTISTA, IGOR LUCHINI; RIANI, LUIZ AUGUSTO; GONCALVES, LIVIA DE SOUZA; SALE, CRAIG; GENNARI DE MEDEIROS, MARISA HELENA; GUALANO, BRUNO; et al. The role of chronic muscle (in)activity on carnosine homeostasis: a study with spinal cord-injured athletes. AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, v. 320, n. 6, p. R824-R832, . (14/11948-8, 19/25032-9, 17/13552-2, 13/07937-8, 15/23176-2, 13/14746-4, 19/12236-5)
SILVA, VINICIUS DA EIRA; PAINELLI, VITOR DE SALLES; SHINJO, SAMUEL KATSUYUKI; PEREIRA, WAGNER RIBEIRO; CILLI, EDUARDO MAFFUD; SALE, CRAIG; GUALANO, BRUNO; OTADUY, MARIA CONCEPCION; ARTIOLI, GUILHERME GIANNINI. Magnetic Resonance Spectroscopy as a Non-invasive Method to Quantify Muscle Carnosine in Humans: a Comprehensive Validity Assessment. SCIENTIFIC REPORTS, v. 10, n. 1, . (13/04806-0, 14/11948-8, 13/14746-4)
TRITTO, ALINE C.; BUENO, SALOMAO; RODRIGUES, ROSA M. P.; GUALANO, BRUNO; ROSCHEL, HAMILTON; ARTIOLI, GUILHERME G.. Negligible Effects of beta-Hydroxy-beta-Methylbutyrate Free Acid and Calcium Salt on Strength and Hypertrophic Responses to Resistance Training: A Randomized, Placebo-Controlled Study. INTERNATIONAL JOURNAL OF SPORT NUTRITION AND EXERCISE METABOLISM, v. 29, n. 5, p. 505-511, . (14/11948-8)
ARTIOLI, GUILHERME GIANNINI; SALE, CRAIG; JONES, REBECCA LOUISE. Carnosine in health and disease. European Journal of Sport Science, v. 19, n. 1, SI, p. 30-39, . (14/11948-8)
GONCALVES, LIVIA DE SOUZA; SALES, LUCAS PEIXOTO; SAITO, TIEMI RAQUEL; CAMPOS, JULIANE CRUZ; FERNANDES, ALAN LINS; NATALI, JOSE; JENSEN, LEONARDO; ARNOLD, ALEXANDRE; RAMALHO, LISLEY; BECHARA, LUIZ ROBERTO GRASSMANN; et al. Histidine dipeptides are key regulators of excitation-contraction coupling in cardiac muscle: Evidence from a novel CARNS1 knockout rat model. REDOX BIOLOGY, v. 44, . (17/16540-5, 13/14746-4, 17/11142-1, 13/07937-8, 17/13552-2, 19/24899-9, 18/14544-6, 19/25032-9, 14/11948-8, 20/04006-7)
SANTOS, LIVIA; GONCALVES, L. S.; BAGHERI-HANEI, SHIRIN; MOLLER, GABRIELLA BERWIG; SALE, CRAIG; JAMES, RUTH M.; ARTIOLI, GUILHERME GIANNINI. Insulin stimulates beta-alanine uptake in skeletal muscle cells in vitro. Amino Acids, v. 53, n. 11, . (14/11948-8, 19/25032-9)
LANCHA JUNIOR, ANTONIO HERBERT; PAINELLI, VITOR DE SALLES; SAUNDERS, BRYAN; ARTIOLI, GUILHERME GIANNINI. Nutritional Strategies to Modulate Intracellular and Extracellular Buffering Capacity During High-Intensity Exercise. SPORTS MEDICINE, v. 45, n. 1, p. S71-S81, . (11/17059-2, 13/04806-0, 10/11221-0, 14/11948-8)
KRATZ, CAROLINE DE ANDRADE; PAINELLI, VITOR DE SALLES; DE ANDRADE NEMEZIO, KLEINER MARCIO; DA SILVA, RAFAEL PIRES; FRANCHINI, EMERSON; ZAGATTO, ALESSANDRO MOURA; GUALANO, BRUNO; ARTIOLI, GUILHERME GIANNINI. Beta-alanine supplementation enhances judo-related performance in highly-trained athletes. JOURNAL OF SCIENCE AND MEDICINE IN SPORT, v. 20, n. 4, p. 403-408, . (13/04806-0, 14/11948-8, 13/14746-4)
SAUNDERS, BRYAN; ELLIOTT-SALE, KIRSTY; ARTIOLI, GUILHERME G.; SWINTON, PAUL A.; DOLAN, EIMEAR; ROSCHEL, HAMILTON; SALE, CRAIG; GUALANO, BRUNO. beta-alanine supplementation to improve exercise capacity and performance: a systematic review and meta-analysis. BRITISH JOURNAL OF SPORTS MEDICINE, v. 51, n. 8, p. 658+, . (14/11948-8, 15/11328-2, 13/14746-4)
DA SILVA, RAFAEL PIRES; DE OLIVEIRA, LUANA FARIAS; SAUNDERS, BRYAN; KRATZ, CAROLINE DE ANDRADE; PAINELLI, VITOR DE SALLES; SILVA, VINICIUS DA EIRA; BOUZAS MARINS, JOAO CARLOS; FRANCHINI, EMERSON; GUALANO, BRUNO; ARTIOLI, GUILHERME GIANNINI. Effects of -alanine and sodium bicarbonate supplementation on the estimated energy system contribution during high-intensity intermittent exercise. Amino Acids, v. 51, n. 1, p. 83-96, . (16/50438-0, 12/13026-5, 13/04806-0, 13/14746-4, 14/11948-8)
PAINELLI, VITOR DE SALLES; NEMEZIO, KLEINER MARCIO; PINTO, ANA JESSICA; FRANCHI, MARIANA; ANDRADE, ISABEL; RIANI, LUIZ AUGUSTO; SAUNDERS, BRYAN; SALE, CRAIG; HARRIS, ROGER CHARLES; GUALANO, BRUNO; et al. High-Intensity Interval Training Augments Muscle Carnosine in the Absence of Dietary Beta-alanine Intake. MEDICINE AND SCIENCE IN SPORTS AND EXERCISE, v. 50, n. 11, p. 2242-2252, . (13/04806-0, 16/50438-0, 14/11948-8, 13/14746-4)
CARVALHO, VICTOR H.; OLIVEIRA, ANA H. S.; DE OLIVEIRA, LUANA F.; DA SILVA, RAFAEL P.; DI MASCIO, PAOLO; GUALANO, BRUNO; ARTIOLI, GUILHERME G.; MEDEIROS, MARISA H. G.. Exercise and beta-alanine supplementation on carnosine-acrolein adduct in skeletal muscle. REDOX BIOLOGY, v. 18, p. 222-228, . (13/07937-8, 16/24761-9, 14/11948-8, 13/14746-4)
DE OLIVEIRA, LUANA FARIAS; SAUNDERS, BRYAN; ARTIOLI, GUILHERME GIANNINI. Is Bypassing the Stomach a Means to Optimize Sodium Bicarbonate Supplementation? A Case Study With a Postbariatric Surgery Individual. INTERNATIONAL JOURNAL OF SPORT NUTRITION AND EXERCISE METABOLISM, v. 28, n. 6, p. 660-663, . (14/11948-8, 16/50438-0)
SAUNDERS, B.; DE OLIVEIRA, L. F.; DA SILVA, R. P.; DE SALLES PAINELLI, V.; GONCALVES, L. S.; YAMAGUCHI, G.; MUTTI, T.; MACIEL, E.; ROSCHEL, H.; ARTIOLI, G. G.; et al. Placebo in sports nutrition: a proof-of-principle study involving caffeine supplementation. SCANDINAVIAN JOURNAL OF MEDICINE & SCIENCE IN SPORTS, v. 27, n. 11, p. 1240-1247, . (13/04806-0, 11/19513-2, 14/11948-8, 13/14746-4)

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