Perturbations of NAD⁺salvage systems impact mitochondrial function and energy homeostasis in mouse myoblasts and intact skeletal muscle

Dec 7, 2017American journal of physiology. Endocrinology and metabolism

Disrupting NAD+ recycling affects energy production and mitochondria in mouse muscle cells and muscle tissue

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Abstract

NAMPT reduction led to a 70% decrease in NAD levels in muscle cells.

NAMPT knockdown resulted in a 50% decrease in NAD levels and a 25% reduction in maximal respiratory capacity in myoblasts.
Increased anaerobic glycolytic flux by 55% and a 25% rise in glucose uptake were observed in NAMPT-deficient cells.
Restoration of NAD levels with nicotinamide riboside improved maximal respiratory capacity by 32% in knockdown cells.
In floxed Nampt mice, NAMPT and NAD levels decreased by 38% and 43%, respectively, causing a 40% increase in glucose uptake.
Mitochondrial complex IV respiration was compromised by 20% in muscle cells with reduced NAMPT.
Changes in metabolism may be linked to the SIRT6/HIF1α axis as indicated by increased expression of certain regulated genes.

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Nicotinamide adenine dinucleotide (NAD) can be synthesized by nicotinamide phosphoribosyltransferase (NAMPT). We aimed to determine the role of NAMPT in maintaining NADlevels, mitochondrial function, and metabolic homeostasis in skeletal muscle cells. We generated stable Nampt knockdown (sh Nampt KD) C2C12 cells using a shRNA lentiviral approach. Moreover, we applied gene electrotransfer to express Cre recombinase in tibialis anterior muscle of floxed Nampt mice. In sh Nampt KD C2C12 myoblasts, Nampt and NADlevels were reduced by 70% and 50%, respectively, and maximal respiratory capacity was reduced by 25%. Moreover, anaerobic glycolytic flux increased by 55%, and 2-deoxyglucose uptake increased by 25% in sh Nampt KD cells. Treatment with the NADprecursor nicotinamide riboside restored NADlevels in sh Nampt cells and increased maximal respiratory capacity by 18% and 32% in control and sh Nampt KD cells, respectively. Expression of Cre recombinase in muscle of floxed Nampt mice reduced NAMPT and NADlevels by 38% and 43%, respectively. Glucose uptake increased by 40%, and mitochondrial complex IV respiration was compromised by 20%. Hypoxia-inducible factor (HIF)-1α-regulated genes and histone H3 lysine 9 (H3K9) acetylation, a known sirtuin 6 (SIRT6) target, were increased in shNampt KD cells. Thus, we propose that the shift toward glycolytic metabolism observed, at least in part, is mediated by the SIRT6/HIF1α axis. Our findings suggest that NAMPT plays a key role for maintaining NADlevels in skeletal muscle and that NAMPT deficiency compromises oxidative phosphorylation capacity and alters energy homeostasis in this tissue. + + + + + + +

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Perturbations of NAD⁺salvage systems impact mitochondrial function and energy homeostasis in mouse myoblasts and intact skeletal muscle

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