title: Evidence for a direct effect of the NAD+ precursor acipimox on muscle mitochondrial function in humans.
abstract: Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide (NAD(+)) precursors to increase oxidative phosphorylation and improve metabolic health, but human data are lacking. We hypothesize that the nicotinic acid derivative acipimox, an NAD(+) precursor, would directly affect mitochondrial function independent of reductions in nonesterified fatty acid (NEFA) concentrations. In a multicenter randomized crossover trial, 21 patients with type 2 diabetes (age 57.7 ± 1.1 years, BMI 33.4 ± 0.8 kg/m(2)) received either placebo or acipimox 250 mg three times daily dosage for 2 weeks. Acipimox treatment increased plasma NEFA levels (759 ± 44 vs. 1,135 ± 97 μmol/L for placebo vs. acipimox, P < 0.01) owing to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene sets and a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response. Further studies in C2C12 myotubes confirmed a direct effect of acipimox on NAD(+) levels, mitonuclear protein imbalance, and mitochondrial oxidative capacity. To the best of our knowledge, this study is the first to demonstrate that NAD(+) boosters can also directly affect skeletal muscle mitochondrial function in humans.
authors.affiliation: Department of Human Biology, Maastricht University Medical Center, Maastricht, the Netherlands School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Tineke
authors.initials: T
authors.lastname: van de Weijer
authors.affiliation: Department of Human Biology, Maastricht University Medical Center, Maastricht, the Netherlands Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Phielix
authors.affiliation: Department of Human Biology, Maastricht University Medical Center, Maastricht, the Netherlands School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Lena
authors.initials: L
authors.lastname: Bilet
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Evan G
authors.initials: EG
authors.lastname: Williams
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Ropelle
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bierwagen
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany.
authors.forename: Roshan
authors.initials: R
authors.lastname: Livingstone
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nowotny
authors.affiliation: Department of Human Biology, Maastricht University Medical Center, Maastricht, the Netherlands School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Sparks
authors.affiliation: Department of Human Biology, Maastricht University Medical Center, Maastricht, the Netherlands School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Sabina
authors.initials: S
authors.lastname: Paglialunga
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Szendroedi
authors.affiliation: School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Bas
authors.initials: B
authors.lastname: Havekes
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Norman
authors.initials: N
authors.lastname: Moullan
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, Kuopio, Finland.
authors.forename: Eija
authors.initials: E
authors.lastname: Pirinen
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany.
authors.forename: Jong-Hee
authors.initials: JH
authors.lastname: Hwang
authors.affiliation: School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands Department of Radiology, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Vera B
authors.initials: VB
authors.lastname: Schrauwen-Hinderling
authors.affiliation: School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands Department of Human Movement Sciences, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Matthijs K C
authors.initials: MK
authors.lastname: Hesselink
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, University Hospital Düsseldorf, Düsseldorf, Germany German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany michael.roden@ddz.uni-duesseldorf.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Roden
authors.affiliation: Department of Human Biology, Maastricht University Medical Center, Maastricht, the Netherlands School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands p.schrauwen@maastrichtuniversity.nl.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schrauwen
mesh_terms: D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*
chemical_list: D000960:Hypolipidemic Agents; D011719:Pyrazines; C027696:acipimox