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

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  • Astrid L Basse, Københavns Universitet
  • ,
  • Marianne Agerholm, Københavns Universitet
  • ,
  • Jean Farup
  • Emilie Dalbram, Københavns Universitet
  • ,
  • Joachim Nielsen, Syddansk Universitet
  • ,
  • Niels Ørtenblad, Syddansk Universitet
  • ,
  • Ali Altıntaş, Københavns Universitet
  • ,
  • Amy M Ehrlich, Københavns Universitet
  • ,
  • Thomas Krag, Copenhagen Neuromuscular Center, Rigshospitalet, Copenhagen
  • ,
  • Santina Bruzzone, Department of Experimental Medicine, University of Genova, Genova
  • ,
  • Morten Dall, Københavns Universitet
  • ,
  • Roldan M de Guia, Københavns Universitet
  • ,
  • 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, Københavns Universitet
  • ,
  • 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, Københavns Universitet

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.

OriginalsprogEngelsk
Artikelnummer101271
TidsskriftMolecular Metabolism
Vol/bind53
Antal sider19
ISSN2212-8778
DOI
StatusUdgivet - nov. 2021

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