Limna - Lausanne Integrative Metabolism Nutrition Alliance

SEMINAR

Tuesday 27th June 2017
14h - EPFL – room AI.1153*

Metabolic effects of NAD deficiency and effectiveness of supplemental precursors in skeletal muscle


Prof. Joseph Baur, PhD

Department of Physiology and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104

Host: Dr. Carles Cantó
 
(*) IMPORTANT NOTICE: People with no access to AI 1153 can meet at SV Reception/Welcome Desk. A person will be there to pick you up at 13:55. 
 

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 or metabolic stress and over the course of natural aging. We examined the metabolic consequences of specifically depleting Nampt, an essential enzyme in the NAD salvage pathway in muscle. 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. The limited effectiveness of orally delivered NR appears to be due to metabolism in the liver, as intravenous administration fully rescued intramuscular NAD levels. We employ tracer studies to compare the effectiveness of supplementing with NR vs NMN to increase intramuscular NAD, and to establish that intact nucleotides contribute to the mitochondrial NAD pool. Finally, 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.