| First Author | Agerholm M | Year | 2018 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 314 |
| Issue | 4 | Pages | E377-E395 |
| PubMed ID | 29208611 | Mgi Jnum | J:261991 |
| Mgi Id | MGI:6157160 | Doi | 10.1152/ajpendo.00213.2017 |
| Citation | Agerholm M, et al. (2018) Perturbations of NAD(+) salvage systems impact mitochondrial function and energy homeostasis in mouse myoblasts and intact skeletal muscle. Am J Physiol Endocrinol Metab 314(4):E377-E395 |
| abstractText | Nicotinamide adenine dinucleotide (NAD(+)) can be synthesized by nicotinamide phosphoribosyltransferase (NAMPT). We aimed to determine the role of NAMPT in maintaining NAD(+) levels, 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 NAD(+) levels 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 NAD(+) precursor nicotinamide riboside restored NAD(+) levels 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 NAD(+) levels by 38% and 43%, respectively. Glucose uptake increased by 40%, and mitochondrial complex IV respiration was compromised by 20%. Hypoxia-inducible factor (HIF)-1alpha-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/HIF1alpha axis. Our findings suggest that NAMPT plays a key role for maintaining NAD(+) levels in skeletal muscle and that NAMPT deficiency compromises oxidative phosphorylation capacity and alters energy homeostasis in this tissue. |
