Genetic Ablation of CD38 Protects against Western Diet-Induced Exercise Intolerance and Metabolic Inflexibility.
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.
Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709, United States of America.
Shian-Huey
SH
Chiang
Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709, United States of America.
W Wallace
WW
Harrington
Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709, United States of America.
Guizhen
G
Luo
Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709, United States of America.
Naphtali O
NO
Milliken
Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709, United States of America.
John C
JC
Ulrich
QSCI Computational Biology, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709, United States of America.
Jing
J
Chen
QSCI Computational Biology, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709, United States of America.
Deepak K
DK
Rajpal
Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709, United States of America.
Ying
Y
Qian
Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709, United States of America.
Tiffany
T
Carpenter
Laboratory Animal Science, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709, United States of America.
Rusty
R
Murray
Target & Pathway Validation, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709, United States of America.
Robert S
RS
Geske
Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709, United States of America.
Stephen A
SA
Stimpson
Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709, United States of America.
Henning F
HF
Kramer
Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709, United States of America.
Curt D
CD
Haffner
Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709, United States of America.
J David
JD
Becherer
Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709, United States of America.
Frank
F
Preugschat
Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709, United States of America.
Andrew N
AN
Billin
D036541:ADP-ribosyl Cyclase / Q000378:metabolism; D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D036563:Cyclic ADP-Ribose / Q000378:metabolism; D066273:Diet, Western / Q000009:adverse effects*; D008297:Male; D008659:Metabolic Diseases / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D010805:Physical Conditioning, Animal / Q000502:physiology*
D009243:NAD; D036563:Cyclic ADP-Ribose; D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1