Nampt controls skeletal muscle development by maintaining Ca2+ homeostasis and mitochondrial integrity
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Nampt controls skeletal muscle development by maintaining Ca2+ 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.
In: Molecular Metabolism, Vol. 53, 101271, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Nampt controls skeletal muscle development by maintaining Ca2+ homeostasis and mitochondrial integrity
AU - Basse, Astrid L.
AU - Agerholm, Marianne
AU - Farup, Jean
AU - Dalbram, Emilie
AU - Nielsen, Joachim
AU - Ørtenblad, Niels
AU - Altıntaş, Ali
AU - Ehrlich, Amy M.
AU - Krag, Thomas
AU - Bruzzone, Santina
AU - Dall, Morten
AU - de Guia, Roldan M.
AU - Jensen, Jonas B.
AU - Møller, Andreas B.
AU - Karlsen, Anders
AU - Kjær, Michael
AU - Barrès, Romain
AU - Vissing, John
AU - Larsen, Steen
AU - Jessen, Niels
AU - Treebak, Jonas T.
N1 - Publisher Copyright: © 2021 The Author(s)
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Cyclophilin D
KW - Mitochondrial permeability transition pore (mPTP)
KW - Myopathy
KW - NAD
KW - Nicotinamide riboside
KW - Sarcopenia
U2 - 10.1016/j.molmet.2021.101271
DO - 10.1016/j.molmet.2021.101271
M3 - Journal article
C2 - 34119711
AN - SCOPUS:85108978816
VL - 53
JO - Molecular Metabolism
JF - Molecular Metabolism
SN - 2212-8778
M1 - 101271
ER -
ID: 273702264