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Nampt controls skeletal muscle development by maintaining Ca(2+) homeostasis and mitochondrial integrity
OBJECTIVE: NAD(+) is a co-factor and substrate for enzymes maintaining energy homeostasis. Nicotinamide phosphoribosyltransferase (NAMPT) controls NAD(+) synthesis, and in skeletal muscle, NAD(+) is essential for muscle integrity. However, the underlying molecular mechanisms by which NAD(+) synthesi...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259345/ https://www.ncbi.nlm.nih.gov/pubmed/34119711 http://dx.doi.org/10.1016/j.molmet.2021.101271 |
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author | Basse, Astrid L. Agerholm, Marianne Farup, Jean Dalbram, Emilie Nielsen, Joachim Ørtenblad, Niels Altıntaş, Ali Ehrlich, Amy M. Krag, Thomas Bruzzone, Santina Dall, Morten de Guia, Roldan M. Jensen, Jonas B. Møller, Andreas B. Karlsen, Anders Kjær, Michael Barrès, Romain Vissing, John Larsen, Steen Jessen, Niels Treebak, Jonas T. |
author_facet | Basse, Astrid L. Agerholm, Marianne Farup, Jean Dalbram, Emilie Nielsen, Joachim Ørtenblad, Niels Altıntaş, Ali Ehrlich, Amy M. Krag, Thomas Bruzzone, Santina Dall, Morten de Guia, Roldan M. Jensen, Jonas B. Møller, Andreas B. Karlsen, Anders Kjær, Michael Barrès, Romain Vissing, John Larsen, Steen Jessen, Niels Treebak, Jonas T. |
author_sort | Basse, Astrid L. |
collection | PubMed |
description | OBJECTIVE: NAD(+) is a co-factor and substrate for enzymes maintaining energy homeostasis. Nicotinamide phosphoribosyltransferase (NAMPT) controls NAD(+) synthesis, and in skeletal muscle, NAD(+) is essential for muscle integrity. However, the underlying molecular mechanisms by which NAD(+) synthesis affects muscle health remain poorly understood. Thus, the objective of the current study was to delineate the role of NAMPT-mediated NAD(+) biosynthesis in skeletal muscle development and function. METHODS: To determine the role of Nampt in muscle development and function, we generated skeletal muscle-specific Nampt KO (SMNKO) mice. We performed a comprehensive phenotypic characterization of the SMNKO mice, including metabolic measurements, histological examinations, and RNA sequencing analyses of skeletal muscle from SMNKO mice and WT littermates. RESULTS: SMNKO mice were smaller, with phenotypic changes in skeletal muscle, including reduced fiber area and increased number of centralized nuclei. The majority of SMNKO mice died prematurely. Transcriptomic analysis identified that the gene encoding the mitochondrial permeability transition pore (mPTP) regulator Cyclophilin D (Ppif) was upregulated in skeletal muscle of SMNKO mice from 2 weeks of age, with associated increased sensitivity of mitochondria to the Ca(2+)-stimulated mPTP opening. Treatment of SMNKO mice with the Cyclophilin D inhibitor, Cyclosporine A, increased membrane integrity, decreased the number of centralized nuclei, and increased survival. CONCLUSIONS: Our study demonstrates that NAMPT is crucial for maintaining cellular Ca(2+) homeostasis and skeletal muscle development, which is vital for juvenile survival. |
format | Online Article Text |
id | pubmed-8259345 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-82593452021-07-12 Nampt controls skeletal muscle development by maintaining Ca(2+) homeostasis and mitochondrial integrity Basse, Astrid L. Agerholm, Marianne Farup, Jean Dalbram, Emilie Nielsen, Joachim Ørtenblad, Niels Altıntaş, Ali Ehrlich, Amy M. Krag, Thomas Bruzzone, Santina Dall, Morten de Guia, Roldan M. Jensen, Jonas B. Møller, Andreas B. Karlsen, Anders Kjær, Michael Barrès, Romain Vissing, John Larsen, Steen Jessen, Niels Treebak, Jonas T. Mol Metab Original Article OBJECTIVE: NAD(+) is a co-factor and substrate for enzymes maintaining energy homeostasis. Nicotinamide phosphoribosyltransferase (NAMPT) controls NAD(+) synthesis, and in skeletal muscle, NAD(+) is essential for muscle integrity. However, the underlying molecular mechanisms by which NAD(+) synthesis affects muscle health remain poorly understood. Thus, the objective of the current study was to delineate the role of NAMPT-mediated NAD(+) biosynthesis in skeletal muscle development and function. METHODS: To determine the role of Nampt in muscle development and function, we generated skeletal muscle-specific Nampt KO (SMNKO) mice. We performed a comprehensive phenotypic characterization of the SMNKO mice, including metabolic measurements, histological examinations, and RNA sequencing analyses of skeletal muscle from SMNKO mice and WT littermates. RESULTS: SMNKO mice were smaller, with phenotypic changes in skeletal muscle, including reduced fiber area and increased number of centralized nuclei. The majority of SMNKO mice died prematurely. Transcriptomic analysis identified that the gene encoding the mitochondrial permeability transition pore (mPTP) regulator Cyclophilin D (Ppif) was upregulated in skeletal muscle of SMNKO mice from 2 weeks of age, with associated increased sensitivity of mitochondria to the Ca(2+)-stimulated mPTP opening. Treatment of SMNKO mice with the Cyclophilin D inhibitor, Cyclosporine A, increased membrane integrity, decreased the number of centralized nuclei, and increased survival. CONCLUSIONS: Our study demonstrates that NAMPT is crucial for maintaining cellular Ca(2+) homeostasis and skeletal muscle development, which is vital for juvenile survival. Elsevier 2021-06-11 /pmc/articles/PMC8259345/ /pubmed/34119711 http://dx.doi.org/10.1016/j.molmet.2021.101271 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Basse, Astrid L. Agerholm, Marianne Farup, Jean Dalbram, Emilie Nielsen, Joachim Ørtenblad, Niels Altıntaş, Ali Ehrlich, Amy M. Krag, Thomas Bruzzone, Santina Dall, Morten de Guia, Roldan M. Jensen, Jonas B. Møller, Andreas B. Karlsen, Anders Kjær, Michael Barrès, Romain Vissing, John Larsen, Steen Jessen, Niels Treebak, Jonas T. Nampt controls skeletal muscle development by maintaining Ca(2+) homeostasis and mitochondrial integrity |
title | Nampt controls skeletal muscle development by maintaining Ca(2+) homeostasis and mitochondrial integrity |
title_full | Nampt controls skeletal muscle development by maintaining Ca(2+) homeostasis and mitochondrial integrity |
title_fullStr | Nampt controls skeletal muscle development by maintaining Ca(2+) homeostasis and mitochondrial integrity |
title_full_unstemmed | Nampt controls skeletal muscle development by maintaining Ca(2+) homeostasis and mitochondrial integrity |
title_short | Nampt controls skeletal muscle development by maintaining Ca(2+) homeostasis and mitochondrial integrity |
title_sort | nampt controls skeletal muscle development by maintaining ca(2+) homeostasis and mitochondrial integrity |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259345/ https://www.ncbi.nlm.nih.gov/pubmed/34119711 http://dx.doi.org/10.1016/j.molmet.2021.101271 |
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