Nampt controls skeletal muscle development by maintaining Ca2+ homeostasis and mitochondrial integrity

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  • Astrid L Basse, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen
  • ,
  • Marianne Agerholm, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen
  • ,
  • Jean Farup
  • Emilie Dalbram, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen
  • ,
  • Joachim Nielsen, Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense
  • ,
  • Niels Ørtenblad, Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense
  • ,
  • Ali Altıntaş, The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen
  • ,
  • Amy M Ehrlich, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen
  • ,
  • Thomas Krag, Copenhagen Neuromuscular Center, Rigshospitalet, Copenhagen
  • ,
  • Santina Bruzzone, Department of Experimental Medicine, University of Genova, Genova
  • ,
  • Morten Dall, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen
  • ,
  • Roldan M de Guia, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen
  • ,
  • Jonas B Jensen
  • Andreas B Møller
  • Anders Karlsen, Institute of Sports Medicine, Bispebjerg Hospital, University of Copenhagen, Copenhagen
  • ,
  • Michael Kjær, Institute of Sports Medicine, Bispebjerg Hospital, University of Copenhagen, Copenhagen
  • ,
  • Romain Barrès, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen
  • ,
  • John Vissing, Copenhagen Neuromuscular Center, Rigshospitalet, Copenhagen
  • ,
  • Steen Larsen, Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen
  • ,
  • Niels Jessen
  • Jonas T Treebak, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen

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 important 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 are smaller, with phenotypic changes in skeletal muscle, including reduced fiber area and increased number of centralized nuclei. The majority of SMNKO mice die prematurely. Transcriptomic analysis identified that the gene encoding the mitochondrial permeability transition pore (mPTP) regulator Cyclophilin D (Ppif) is upregulated in skeletal muscle of SMNKO mice from 2 weeks of age, with associated increased sensitivity of mitochondria to 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.

CONCLUSION: Our study demonstrates that NAMPT is crucial for maintaining cellular Ca2+ homeostasis and skeletal muscle development, which is vital for juvenile survival.

Original languageEnglish
Article number101271
JournalMolecular Metabolism
Volume53
Number of pages19
ISSN2212-8778
DOIs
Publication statusPublished - Nov 2021

    Research areas

  • Cyclophilin D, Mitochondrial permeability transition pore (mPTP), Myopathy, NAD, Nicotinamide riboside, Sarcopenia

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