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

Gonçalves, L.S., Sales, L.P., Saito, T.R., Campos, J.C., Fernandes, A.L., Natali, J., Jensen, L., Arnold, A., Ramalho, L., Bechara, L.R.G., Esteca, M.V., Correa, I., Sant'Anna, D., Ceroni, A., Michelini, L.C., Gualano, B., Teodoro, W., Carvalho, V.H., Vargas, B.S., Medeiros, M.H.G., Baptista, I.L., Irigoyen, M.C., Sale, C. ORCID: 0000-0002-5816-4169, Ferreira, J.C.B. and Artioli, G.G., 2021. Histidine dipeptides are key regulators of excitation-contraction coupling in cardiac muscle: evidence from a novel CARNS1 knockout rat model. Redox Biology, 44: 102016. ISSN 2213-2317

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Abstract

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.

Item Type: Journal article
Publication Title: Redox Biology
Creators: Gonçalves, L.S., Sales, L.P., Saito, T.R., Campos, J.C., Fernandes, A.L., Natali, J., Jensen, L., Arnold, A., Ramalho, L., Bechara, L.R.G., Esteca, M.V., Correa, I., Sant'Anna, D., Ceroni, A., Michelini, L.C., Gualano, B., Teodoro, W., Carvalho, V.H., Vargas, B.S., Medeiros, M.H.G., Baptista, I.L., Irigoyen, M.C., Sale, C., Ferreira, J.C.B. and Artioli, G.G.
Publisher: Elsevier BV
Date: August 2021
Volume: 44
ISSN: 2213-2317
Identifiers:
NumberType
10.1016/j.redox.2021.102016DOI
1442309Other
Rights: © 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Divisions: Schools > School of Science and Technology
Record created by: Laura Ward
Date Added: 28 May 2021 15:32
Last Modified: 31 May 2021 15:02
URI: http://irep.ntu.ac.uk/id/eprint/42954

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