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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Histidine dipeptides are key regulators of excitation-contraction coupling in cardiac muscle: Evidence from a novel CARNS1 knockout rat model

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Goncalves, Livia de Souza [1, 2] ; Sales, Lucas Peixoto [1, 2] ; Saito, Tiemi Raquel [1, 2] ; Campos, Juliane Cruz [3] ; Fernandes, Alan Lins [1, 2] ; Natali, Jose [2] ; Jensen, Leonardo [4] ; Arnold, Alexandre [5, 4] ; Ramalho, Lisley [3, 5] ; Bechara, Luiz Roberto Grassmann [3] ; Esteca, Marcos Vinicius [6] ; Correa, Isis [4] ; Sant'Anna, Diogo [4] ; Ceroni, Alexandre ; Michelini, Lisete Compagno ; Gualano, Bruno ; Teodoro, Walcy [1] ; Carvalho, Victor Henrique [7] ; Vargas, Bianca Scigliano [7] ; Medeiros, Marisa Helena Gennari [7] ; Baptista, Igor Luchini [6] ; Irigoyen, Maria Claudia [4] ; Sale, Craig [8] ; Ferreira, Julio Cesar Batista [3] ; Artioli, Guilherme Giannini [1, 2]
Total Authors: 25
[1] Univ Sao Paulo, Fac Med FMUSP, Rheumatol Div, Sao Paulo - Brazil
[2] Univ Sao Paulo, Div Reumatol, Fac Med, Appl Physiol & Nutr Res Grp, Sch Phys Educ & Sport, Av Prof Mello Moraes 65, BR-05508030 Sao Paulo, SP - Brazil
[3] Univ Sao Paulo, Inst Biomed Sci, Sao Paulo - Brazil
[4] Univ Sao Paulo, Fac Med, Inst Coracao, Lab Hipertensao, Hosp Clin, Sao Paulo - Brazil
[5] Univ Sao Paulo, Inst Ciencias Biomed, Dept Fisiol, Sao Paulo - Brazil
[6] Univ Estadual Campinas, Fac Ciencias Aplicadas, Lab Cell & Tissue Biol, Campinas - Brazil
[7] Univ Sao Paulo, Inst Quim, Dept Bioquim, Sao Paulo - Brazil
[8] Nottingham Trent Univ, Sport Hlth & Performance Enhancement Res Ctr, Musculoskeletal Physiol Res Grp, Nottingham - England
Total Affiliations: 8
Document type: Journal article
Source: REDOX BIOLOGY; v. 44, AUG 2021.
Web of Science Citations: 0

Histidine-containing dipeptides (HCDs) are abundantly expressed in striated muscles. Although important properties have been ascribed to HCDs, including H+ buffering, regulation of Ca2+ transients and protection against oxidative stress, it remains unknown whether they play relevant functions in vivo. To investigate the in vivo roles of HCDs, we developed the first carnosine synthase knockout (CARNS1-/-) rat strain to investigate the impact of an absence of HCDs on skeletal and cardiac muscle function. Male wild-type (WT) and knockout rats (4 months-old) were used. Skeletal muscle function was assessed by an exercise tolerance test, contractile function in situ and muscle buffering capacity in vitro. Cardiac function was assessed in vivo by echocardiography and cardiac electrical activity by electrocardiography. Cardiomyocyte contractile function was assessed in isolated cardiomyocytes by measuring sarcomere contractility, along with the determination of Ca2+ transient. Markers of oxidative stress, mitochondrial function and expression of proteins were also evaluated in cardiac muscle. Animals were supplemented with carnosine (1.8% in drinking water for 12 weeks) in an attempt to rescue tissue HCDs levels and function. CARNS1-/- resulted in the complete absence of carnosine and anserine, but it did not affect exercise capacity, skeletal muscle force production, fatigability or buffering capacity in vitro, indicating that these are not essential for pH regulation and function in skeletal muscle. In cardiac muscle, however, CARNS1-/- resulted in a significant impairment of contractile function, which was confirmed both in vivo and ex vivo in isolated sarcomeres. Impaired systolic and diastolic dysfunction were accompanied by reduced intracellular Ca2+ peaks and slowed Ca2+ removal, but not by increased markers of oxidative stress or impaired mitochondrial respiration. No relevant increases in muscle carnosine content were observed after carnosine supplementation. Results show that a primary function of HCDs in cardiac muscle is the regulation of Ca2+ handling and excitation-contraction coupling. (AU)

FAPESP's process: 17/16540-5 - Exercise, lifespan and healthspan: a molecular and longitudinal approach to study their interactions
Grantee:Juliane Cruz Campos
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 13/14746-4 - Carnosine metabolism in skeletal muscle: a multi-approach study
Grantee:Bruno Gualano
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 17/11142-1 - Mitochondrial formyl peptides as signaling molecules: new perspective in the treatment of cardiac ischemia/reperfusion injury.
Grantee:Luiz Roberto Grassmann Bechara
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
Grantee:Ohara Augusto
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 17/13552-2 - Reducing sedentary time in clinical populations: the take a stand for health study
Grantee:Bruno Gualano
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 19/24899-9 - Role of reactive aldehydes in cigarette smoke DNA damage and detoxification mechanisms in lungs and heart: development of urinary biomarkers of exposure
Grantee:Bianca Scigliano Vargas
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 18/14544-6 - Blood-brain barrier: a new paradigm in the treatment of hypertension
Grantee:Lisete Compagno Michelini
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 19/25032-9 - The role of carnosine on Ca2+ handling, control of oxidative stress and protection against protein glycation: advances and applications of the study life without carnosine
Grantee:Hamilton Augusto Roschel da Silva
Support Opportunities: Regular Research Grants
FAPESP's process: 14/11948-8 - 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
Grantee:Guilherme Giannini Artioli
Support Opportunities: Research Grants - Young Investigators Grants
FAPESP's process: 20/04006-7 - SAMbA: a novel therapeutic strategy for heart failure with preserved ejection fraction (HFpEF)
Grantee:Lisley Santos Ramalho
Support Opportunities: Scholarships in Brazil - Master