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Genetic Ablation of CD38 Protects against Western Diet-Induced Exercise Intolerance and Metabolic Inflexibility

2015; Public Library of Science; Volume: 10; Issue: 8 Linguagem: Inglês

10.1371/journal.pone.0134927

1932-6203

Shian-Huey Chiang, W. Wallace Harrington, Guizhen Luo, Naphtali Milliken, John C. Ulrich, Jing Chen, Deepak K. Rajpal, Ying Qian, Tiffany Carpenter, Rusty Murray, Robert S. Geske, Stephen A. Stimpson, Henning F. Kramer, Curt D. Haffner, J. David Becherer, Frank Preugschat, Andrew N. Billin,

PARP inhibition in cancer therapy

Nicotinamide adenine dinucleotide (NAD+) is a key cofactor required for essential metabolic oxidation-reduction reactions. It also regulates various cellular activities, including gene expression, signaling, DNA repair and calcium homeostasis. Intracellular NAD+ levels are tightly regulated and often respond rapidly to nutritional and environmental changes. Numerous studies indicate that elevating NAD+ may be therapeutically beneficial in the context of numerous diseases. However, the role of NAD+ on skeletal muscle exercise performance is poorly understood. CD38, a multi-functional membrane receptor and enzyme, consumes NAD+ to generate products such as cyclic-ADP-ribose. CD38 knockout mice show elevated tissue and blood NAD+ level. Chronic feeding of high-fat, high-sucrose diet to wild type mice leads to exercise intolerance and reduced metabolic flexibility. Loss of CD38 by genetic mutation protects mice from diet-induced metabolic deficit. These animal model results suggest that elevation of tissue NAD+ through genetic ablation of CD38 can profoundly alter energy homeostasis in animals that are maintained on a calorically-excessive Western diet.