Nampt controls skeletal muscle development by maintaining Ca2+ 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+ synthesis affect...
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Format: | Article |
Language: | English |
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Elsevier
2021-11-01
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Series: | Molecular Metabolism |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877821001162 |
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doaj-63c9ea19f4734bf483736116a2789e45 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Astrid L. Basse Marianne Agerholm Jean Farup Emilie Dalbram Joachim Nielsen Niels Ørtenblad Ali Altıntaş Amy M. Ehrlich Thomas Krag Santina Bruzzone Morten Dall Roldan M. de Guia Jonas B. Jensen Andreas B. Møller Anders Karlsen Michael Kjær Romain Barrès John Vissing Steen Larsen Niels Jessen Jonas T. Treebak |
spellingShingle |
Astrid L. Basse Marianne Agerholm Jean Farup Emilie Dalbram Joachim Nielsen Niels Ørtenblad Ali Altıntaş Amy M. Ehrlich Thomas Krag Santina Bruzzone Morten Dall Roldan M. de Guia Jonas B. Jensen Andreas B. Møller Anders Karlsen Michael Kjær Romain Barrès John Vissing Steen Larsen Niels Jessen Jonas T. Treebak Nampt controls skeletal muscle development by maintaining Ca2+ homeostasis and mitochondrial integrity Molecular Metabolism Cyclophilin D Mitochondrial permeability transition pore (mPTP) Myopathy NAD+ Nicotinamide riboside Sarcopenia |
author_facet |
Astrid L. Basse Marianne Agerholm Jean Farup Emilie Dalbram Joachim Nielsen Niels Ørtenblad Ali Altıntaş Amy M. Ehrlich Thomas Krag Santina Bruzzone Morten Dall Roldan M. de Guia Jonas B. Jensen Andreas B. Møller Anders Karlsen Michael Kjær Romain Barrès John Vissing Steen Larsen Niels Jessen Jonas T. Treebak |
author_sort |
Astrid L. Basse |
title |
Nampt controls skeletal muscle development by maintaining Ca2+ homeostasis and mitochondrial integrity |
title_short |
Nampt controls skeletal muscle development by maintaining Ca2+ homeostasis and mitochondrial integrity |
title_full |
Nampt controls skeletal muscle development by maintaining Ca2+ homeostasis and mitochondrial integrity |
title_fullStr |
Nampt controls skeletal muscle development by maintaining Ca2+ homeostasis and mitochondrial integrity |
title_full_unstemmed |
Nampt controls skeletal muscle development by maintaining Ca2+ homeostasis and mitochondrial integrity |
title_sort |
nampt controls skeletal muscle development by maintaining ca2+ homeostasis and mitochondrial integrity |
publisher |
Elsevier |
series |
Molecular Metabolism |
issn |
2212-8778 |
publishDate |
2021-11-01 |
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 Ca2+-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 Ca2+ homeostasis and skeletal muscle development, which is vital for juvenile survival. |
topic |
Cyclophilin D Mitochondrial permeability transition pore (mPTP) Myopathy NAD+ Nicotinamide riboside Sarcopenia |
url |
http://www.sciencedirect.com/science/article/pii/S2212877821001162 |
work_keys_str_mv |
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doaj-63c9ea19f4734bf483736116a2789e452021-07-05T04:14:01ZengElsevierMolecular Metabolism2212-87782021-11-0153101271Nampt controls skeletal muscle development by maintaining Ca2+ homeostasis and mitochondrial integrityAstrid L. Basse0Marianne Agerholm1Jean Farup2Emilie Dalbram3Joachim Nielsen4Niels Ørtenblad5Ali Altıntaş6Amy M. Ehrlich7Thomas Krag8Santina Bruzzone9Morten Dall10Roldan M. de Guia11Jonas B. Jensen12Andreas B. Møller13Anders Karlsen14Michael Kjær15Romain Barrès16John Vissing17Steen Larsen18Niels Jessen19Jonas T. Treebak20Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkSteno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, DenmarkNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkDepartment of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, DenmarkDepartment of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, DenmarkNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkCopenhagen Neuromuscular Center, Rigshospitalet, Copenhagen, DenmarkDepartment of Experimental Medicine, University of Genova, Genova, ItalyNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkSteno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, DenmarkSteno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, DenmarkInstitute of Sports Medicine, Bispebjerg Hospital, University of Copenhagen, Copenhagen, DenmarkInstitute of Sports Medicine, Bispebjerg Hospital, University of Copenhagen, Copenhagen, DenmarkNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkCopenhagen Neuromuscular Center, Rigshospitalet, Copenhagen, DenmarkCenter for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Clinical Research Centre, Medical University of Bialystok, Bialystok, PolandSteno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, DenmarkNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Corresponding author.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 Ca2+-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 Ca2+ homeostasis and skeletal muscle development, which is vital for juvenile survival.http://www.sciencedirect.com/science/article/pii/S2212877821001162Cyclophilin DMitochondrial permeability transition pore (mPTP)MyopathyNAD+Nicotinamide ribosideSarcopenia |