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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

Grant number: 14/11948-8
Support type:Research Grants - Young Investigators Grants
Duration: February 01, 2015 - January 31, 2019
Field of knowledge:Health Sciences - Physical Education
Principal Investigator:Guilherme Giannini Artioli
Grantee:Guilherme Giannini Artioli
Home Institution: Escola de Educação Física e Esporte (EEFE). Universidade de São Paulo (USP). São Paulo, SP, Brazil
Assoc. researchers:Antonio Herbert Lancha Junior ; Bruno Gualano ; Edilamar Menezes de Oliveira ; Julio Cesar Batista Ferreira ; Patricia Chakur Brum

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)

Articles published in Agência FAPESP about the research grant
Supplement enhances muscle detoxification in athletes 
Suplemento aumenta detoxificação em músculo de atletas 
Brazilian professor ranked among world's top sports researchers 

Scientific publications (13)
(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)
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 JAN 15 2019. Web of Science Citations: 0.
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, JAN 2 2019. Web of Science Citations: 0.
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, JAN 2019. Web of Science Citations: 0.
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, NOV 2018. Web of Science Citations: 0.
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; ARTIOLI, GUILHERME GIANNINI. 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, NOV 2018. Web of Science Citations: 1.
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, SEP 2018. Web of Science Citations: 2.
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, NOV 2017. Web of Science Citations: 3.
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.; GUALANO, B. 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, NOV 2017. Web of Science Citations: 18.
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; ARTIOLI, GUILHERME GIANNINI; SALE, CRAIG; GUALANO, BRUNO. 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, MAY 2017. Web of Science Citations: 16.
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, APR 2017. Web of Science Citations: 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+, APR 2017. Web of Science Citations: 33.
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 NOV 17 2015. Web of Science Citations: 11.
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, NOV 2015. Web of Science Citations: 15.

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