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A chronic low-dose magnesium L-lactate administration has a beneficial effect on the myocardium and the skeletal muscles

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Abstract

The purpose of this study was to determine whether magnesium L-lactate is responsible for having a beneficial effect on the myocardium and the skeletal muscles and how this substrate acts at the molecular level. Twenty seven young male Wistar rats were supplied with a magnesium L-lactate (L) solution, a magnesium chloride (M) solution and/or water (W) as a vehicle for 10 weeks. The treated animals absorbed the L and M solutions as they wished since they also had free access to water. After 9 weeks of treatment, in vivo cardiac function was determined ultrasonically. The animals were sacrificed at the end of the tenth week of treatment and the heart was perfused according to the Langendorff method by using a technique allowing the determination of cardiomyocyte activity (same coronary flow in the two groups). Blood was collected and skeletal muscles of the hind legs were weighed. The myocardial expressions of the sodium/proton exchange 1 (NHE1) and sodium/calcium exchange 1 (NCX1), intracellular calcium accumulation, myocardial magnesium content, as well as systemic and tissue oxidative stress, were determined. Animals of the L group absorbed systematically a low dose of L-lactate (31.5 ± 4.3 µg/100 g of body weight/day) which was approximately four times higher than that ingested in the W group through the diet supplied. Ex vivo cardiomyocyte contractility and the mass of some skeletal muscles (tibialis anterior) were increased by the L treatment. Myocardial calcium was decreased, as was evidenced by an increase in total CaMKII expression, without any change in the ratio between phosphorylated CaMKII and total CaMKII. Cardiac magnesium tended to be elevated. Our results suggest that the increased intracellular magnesium concentration was related to L-lactate-induced cytosolic acidosis and to the activation of the NHE1/NCX1 axis. Interestingly, systemic oxidative stress was reduced by the L treatment whereas the lipid profile of the animals was unaltered. Taken together, these results suggest that a chronic low-dose L-lactate intake has a beneficial health effect on some skeletal muscles and the myocardium through the activation of the NHE1/NCX1 axis, a decrease in cellular calcium and an increase in cellular magnesium. The treatment can be beneficial for the health of young rodents in relation to chronic oxidative stress-related diseases.

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Abbreviations

AAT:

Abdominal adipose tissue

Ac-SOD2:

Acetylated superoxide dismutase 2

ADP:

Adenosine diphosphate

ATP:

Adenosine triphosphate

CaCl2 :

Calcium chloride

CaMKII:

Calcium calmodulin ATPase II

CaMKIIP:

Calcium calmodulin ATPase II phosphorylated at threonine 287; ATPase II

CAT:

Catalase

CLDML:

Chronic low-dose dietary magnesium L-lactate treatment

CO2 :

Carbon dioxide

CPT1β:

Carnitine palmitoyl-CoA transferase 1β

ddCT:

2-ΔΔCT algorithm

EDL:

Extensor digitorum longus

EDTA:

Ethylene diamine tetraacetic acid

EGTA:

Ethylene guanine tetraacetic acid

FRAP:

Ferric reducing antioxidant power

GPR81:

G protein-coupled receptor 81

GPX:

Glutathione peroxidase

HAD:

Hydroxyacyl coenzyme A dehydrogenase

HDL:

High-density lipoproteins

HEPES:

4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid

HRP:

Horseradish peroxidase

IL-1b:

Interleukin 1β

IL-6:

Interleukin 6

IL-10:

Interleukin 10

KCl:

Potassium chloride

L:

Magnesium L-lactate

LDH:

Lactate dehydrogenase

LDL:

Low-density lipoproteins

LSD:

Least square difference

MCT1:

Monocarboxylate transporter 1

MgSO4 :

Magnesium sulphate

MOPS:

3-Morpholino-1-propanesulfonic acid

mPTP:

Mitochondrial permeability transition pore

mRNA:

Messenger ribonucleic acid

mTOR:

Mechanistic target of rapamycin

NaCl:

Sodium chloride

NAD:

Oxidized nicotinamide adenine dinucleotide

NADH:

Reduced nicotinamide adenine dinucleotide

NaHCO3 :

Sodium carbonate

NHE1:

Sodium/proton exchange-1

NCSS:

Number cruncher statistical software

NCX1:

Sodium/calcium exchange-1

O2 :

Dioxygen

PAT:

Perirenal adipose tissue

PD4K:

Pyruvate dehydrogenase 4 kinase

PDH:

Pyruvate dehydrogenase

PDHP:

Pyruvate dehydrogenase phosphorylated at serine 293

PFK:

Phosphofructokinase

PGC1α:

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

PVDF:

Polyvinylidene fluoride

RNA:

Ribonucleic acid

ROS:

Reactive oxygen species

RPM:

Rotation per min

RT-qPCR:

Real-time quantitative polymerase chain reaction

SDS-PAGE:

Sodium dodecyl sulphate polyacrylamide gel electrophoresis

SEM:

Standard error of the mean

SOD1:

Cytosolic superoxide dismutase

SOD2:

Mitochondrial superoxide dismutase

TA:

Tibialis anterior

TBARS:

Thiobarbituric acid reactive substances

TNF-α:

Tumour necrosis factor alpha

VAT:

Visceral adipose tissue

VDAC:

Voltage-dependent anion channel

W:

Water

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Acknowledgements

The authors warmly thank the staff of the Experimental Unit of Animal Nutrition of the National Institute of Agronomical Research (INRAE) of Theix/Saint-Genès-Champanelle for animal care. They also wish to thank Patricia Mabrut for editing the manuscript.

Funding

This work was supported by the French National Institute of Agronomical Research (INRAE).

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Authors and Affiliations

  1. INRAE, UNH, Unité de Nutrition Humaine, CRNH Auvergne, Université Clermont Auvergne, 28 Place Henri Dunant, 63000, Clermont-Ferrand, France

    Marlène Magalhaes Pinto, Chrystèle Jouve, Jean-Paul Rigaudière, Véronique Patrac & Luc Demaison

  2. INSERM, U1055, Laboratory of Fundamental and Applied Bioenergetics, LBFA, Université Grenoble Alpes, 38000, Grenoble, France

    Hervé Dubouchaud & Isabelle Hininger-Favier

  3. Department of Medical Biochemistry and Molecular Biology, CHU Clermont-Ferrand, 63000, Clermont-Ferrand, France

    Damien Bouvier

  4. CHU Clermont-Ferrand, INRAE, UNH, Université Clermont Auvergne, 63000, Clermont-Ferrand, France

    Stéphane Walrand

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  1. Marlène Magalhaes Pinto
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Contributions

MMP, HD, CJ, JPR, VP, IH-F, DB and LD contributed to the technical part of the study. LD performed the statistical analyses. LD contributed to the study conception and design, analysis and interpretation of data. LD wrote the manuscript; HD and SW revisited it critically and gave final approval of the version to be published.

The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Luc Demaison.

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Ethics approval

All experiments followed the European Union recommendations concerning the care and use of laboratory animals for experimental and scientific purposes. All animal work was approved by the national board of ethics for animal experimentation (authorization Apafis n° 00958.02). The performed research was in compliance with the ARRIVE guidelines on animal research.

Conflict of interest

The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Agronomical Research (INRAE).

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Key points

- Dietary magnesium L-lactate increases myocardial contractility and skeletal muscle mass.

- In the heart, this phenomenon results from increased cellular magnesium.

- Increased magnesium is due to acidosis-induced stimulation of the NHE1/NCX1 axis.

- Dietary magnesium L-lactate can be used to maintain health in physically handicapped people.

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Pinto, M.M., Dubouchaud, H., Jouve, C. et al. A chronic low-dose magnesium L-lactate administration has a beneficial effect on the myocardium and the skeletal muscles. J Physiol Biochem 78, 501–516 (2022). https://doi.org/10.1007/s13105-021-00827-8

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