Epithelial magnesium transport by TRPM6 is essential for prenatal development and adult survival

Ludwig Maximilian University of Munich, Germany
The University of Queensland, Australia
Helmholtz Zentrum Munich, Germany
German Institute of Human Nutrition, Germany
Princeton Institute of Life Sciences, United States
University of Würzburg, Germany
LMU Munich, Germany
Paracelsus Medical University, Austria

Dec 19, 2016

https://doi.org/10.7554/eLife.20914

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Abstract
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Abstract

Mg²⁺ regulates many physiological processes and signalling pathways. However, little is known about the mechanisms underlying the organismal balance of Mg²⁺. Capitalizing on a set of newly generated mouse models, we provide an integrated mechanistic model of the regulation of organismal Mg²⁺ balance during prenatal development and in adult mice by the ion channel TRPM6. We show that TRPM6 activity in the placenta and yolk sac is essential for embryonic development. In adult mice, TRPM6 is required in the intestine to maintain organismal Mg²⁺ balance, but is dispensable in the kidney. Trpm6 inactivation in adult mice leads to shortened lifespan, growth deficit and metabolic alterations indicative of impaired energy balance. Dietary Mg²⁺ supplementation not only rescues all phenotypes displayed by Trpm6-deficient adult mice, but also may extend the lifespan of wildtype mice. Hence, maintenance of organismal Mg²⁺ balance by TRPM6 is crucial for prenatal development and survival to adulthood.

Data availability

The following data sets were generated

1. Chubanov V
2. Gudermann T
(2015) Whole-genome profiling of the liver transcriptome in Trpm6 gene deficient mice and control littermates
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE70457).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=krgbqyaatnmvzun&acc=GSE70457
1. Chubanov V
2. Gudermann T
(2016) Data from: Epithelial magnesium transport by TRPM6 is essential for prenatal development and adult survival
Available at Dryad Digital Repository under a CC0 Public Domain Dedication.

https://doi.org/10.5061/dryad.gs7fv
1. Chubanov V
2. Gudermann T
(2016) Ingenuity Pathway Analysis (IPA) analysis of hepatic transcripts altered in Trpm6-deficient mice
Available at Dryad Digital Repository under a CC0 Public Domain Dedication.

https://doi.org/10.5061/dryad.gs7fv
1. Chubanov V
2. Gudermann T
(2016) Metabolic profiling of the serum, liver and gastrocnemius muscle of Trpm6-deficient mice
Available at Dryad Digital Repository under a CC0 Public Domain Dedication.

https://doi.org/10.5061/dryad.gs7fv
1. Chubanov V
2. Gudermann T
(2016) MATLAB code used for statistical analysis of survival distributions of control and dietary treated mice
Available at Dryad Digital Repository under a CC0 Public Domain Dedication.

https://doi.org/10.5061/dryad.gs7fv

Article and author information

Author details

Vladimir Chubanov

Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Munich, Germany

For correspondence
vladimir.chubanov@lrz.uni-muenchen.de

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-6042-4193
Silvia Ferioli

Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Munich, Germany

Competing interests
The authors declare that no competing interests exist.
Annika Wisnowsky

Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Munich, Germany

Competing interests
The authors declare that no competing interests exist.
David G Simmons

School of Biomedical Sciences, The University of Queensland, St. Lucia, Australia

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4115-9371
Christin Leitzinger

Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum Munich, Neuherberg, Germany

Competing interests
The authors declare that no competing interests exist.
Claudia Einer

Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum Munich, Neuherberg, Germany

Competing interests
The authors declare that no competing interests exist.
Wenke Jonas

Department of Experimental Diabetology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany

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The authors declare that no competing interests exist.
Yuriy Shymkiv

Princeton Institute of Life Sciences, Princeton, United States

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The authors declare that no competing interests exist.
Harald Bartsch

Institute of Pathology, Ludwig Maximilian University of Munich, Munich, Germany

Competing interests
The authors declare that no competing interests exist.
Attila Braun

Department of Vascular Medicine, University Hospital and Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany

Competing interests
The authors declare that no competing interests exist.
Banu Akdogan

Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Munich, Germany

Competing interests
The authors declare that no competing interests exist.
Lorenz Mittermeier

Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Munich, Germany

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The authors declare that no competing interests exist.
Ludmila Sytik

Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Munich, Germany

Competing interests
The authors declare that no competing interests exist.
Friedrich Torben

Genome Analysis Center, Institute of Experimental Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany

Competing interests
The authors declare that no competing interests exist.
Vindi Jurinovic

IBE, LMU Munich, Munich, Germany

Competing interests
The authors declare that no competing interests exist.
Emiel PC van der Vorst

Institute for Cardiovascular Prevention, Ludwig Maximilian University of Munich, Munich, Germany

Competing interests
The authors declare that no competing interests exist.
Christian Weber

Institute for Cardiovascular Prevention, Ludwig Maximilian University of Munich, Munich, Germany

Competing interests
The authors declare that no competing interests exist.
Önder A Yildirim

Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum Munich, Neuherberg, Germany

Competing interests
The authors declare that no competing interests exist.
Karl Sotlar

Institute of Pathology, Paracelsus Medical University, Salzburg, Austria

Competing interests
The authors declare that no competing interests exist.
Annette Schürmann

Department of Experimental Diabetology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany

Competing interests
The authors declare that no competing interests exist.
Susanna Zierler

Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Munich, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4684-0385
Hans Zischka

Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum Munich, Neuherberg, Germany

Competing interests
The authors declare that no competing interests exist.
Alexey G Ryazanov

Princeton Institute of Life Sciences, Princeton, United States

Competing interests
The authors declare that no competing interests exist.
Thomas Gudermann

Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Munich, Germany

For correspondence
thomas.gudermann@lrz.uni-muenchen.de

Competing interests
The authors declare that no competing interests exist.

Funding

Deutsche Forschungsgemeinschaft (TRR 152-P15)

Vladimir Chubanov

Deutsche Forschungsgemeinschaft (TRP 152-P15)

Thomas Gudermann

Deutsche Forschungsgemeinschaft (TRP 152-P14)

Susanna Zierler

Deutsche Forschungsgemeinschaft (SFB1123-A1)

Emiel PC van der Vorst
Christian Weber

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Experiments involving animals were done in accordance with the EU Animal Welfare Act and were approved by the local councils on animal care (permit No 55.2-1-54-2532-134-13 from Government of Oberbayern, Germany, and permit No 2347-15-2014 from State Ministry of Brandenburg, Germany).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.