title: Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle.
abstract: NAD is an obligate co-factor for the catabolism of metabolic fuels in all cell types. However, the availability of NAD in several tissues can become limited during genotoxic stress and the course of natural aging. The point at which NAD restriction imposes functional limitations on tissue physiology remains unknown. We examined this question in murine skeletal muscle by specifically depleting Nampt, an essential enzyme in the NAD salvage pathway. Knockout mice exhibited a dramatic 85% decline in intramuscular NAD content, accompanied by fiber degeneration and progressive loss of both muscle strength and treadmill endurance. Administration of the NAD precursor nicotinamide riboside rapidly ameliorated functional deficits and restored muscle mass despite having only a modest effect on the intramuscular NAD pool. Additionally, lifelong overexpression of Nampt preserved muscle NAD levels and exercise capacity in aged mice, supporting a critical role for tissue-autonomous NAD homeostasis in maintaining muscle mass and function.
authors: Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: David W
authors: DW
authors: Frederick
authors: Department of Physiology and Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Emanuele
authors: E
authors: Loro
authors: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
authors: Ling
authors: L
authors: Liu
authors: Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Antonio
authors: A
authors: Davila
authors: Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Karthikeyani
authors: K
authors: Chellappa
authors: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Ian M
authors: IM
authors: Silverman
authors: Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: William J
authors: WJ
authors: Quinn
authors: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Sager J
authors: SJ
authors: Gosai
authors: Department of Orthopaedic Surgery, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Elisia D
authors: ED
authors: Tichy
authors: Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: James G
authors: JG
authors: Davis
authors: Department of Orthopaedic Surgery, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Foteini
authors: F
authors: Mourkioti
authors: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Brian D
authors: BD
authors: Gregory
authors: ChromaDex Inc., Irvine, CA 92618, USA.
authors: Ryan W
authors: RW
authors: Dellinger
authors: School of Pharmacy, Queen's University Belfast, Belfast, BT9 7BL Northern Ireland, UK.
authors: Philip
authors: P
authors: Redpath
authors: School of Pharmacy, Queen's University Belfast, Belfast, BT9 7BL Northern Ireland, UK.
authors: Marie E
authors: ME
authors: Migaud
authors: Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Eiko
authors: E
authors: Nakamaru-Ogiso
authors: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
authors: Joshua D
authors: JD
authors: Rabinowitz
authors: Department of Physiology and Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Tejvir S
authors: TS
authors: Khurana
authors: Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: baur@mail.med.upenn.edu.
authors: Joseph A
authors: JA
authors: Baur
mesh_terms: D000284:Administration, Oral; D000375:Aging / Q000502:physiology; D000818:Animals; D001682:Biological Availability; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D007249:Inflammation / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D009243:NAD / Q000378:metabolism*; D009336:Necrosis; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D054409:Nicotinamide Phosphoribosyltransferase / Q000172:deficiency / Q000378:metabolism; D009929:Organ Size; D010805:Physical Conditioning, Animal; D011726:Pyridinium Compounds; D014158:Transcription, Genetic
chemical_list: D011726:Pyridinium Compounds; C018613:nicotinamide-beta-riboside; D009243:NAD; D009536:Niacinamide; D054409:Nicotinamide Phosphoribosyltransferase; D005947:Glucose