Sparks 2014 Abstract MiP2014
| NAMPT remodels substrate metabolism in skeletal muscle. |
Link:
MiP2014, Book of Abstracts Open Access
Sparks Lauren M, Stephens NA, Gabriel M, Gardell SJ, Smith SR (2014)
Event: MiP2014
In mammals, nicotinamide phosphoribosyltransferase (NAMPT) is responsible for the first and rate-limiting step in the “salvage pathway” that converts nicotinamide to nicotinamide adenine dinucleotide (NAD+). We previously showed that exercise increased skeletal muscle NAMPT expression, which correlates with mitochondrial content in humans [1]. Caloric restriction-induced beneficial effects in oxidative stress, mitochondrial biogenesis and metabolic adaptation in mice require NAMPT [2]. The mechanisms responsible for metabolic adaption are unclear. We hypothesized that muscle-specific overexpression of NAMPT in mice (NamptTg) would improve muscle respiratory capacity and control and would be additive with endurance exercise training in these mice.
Based on western blotting studies, NamptTg mice express 10-fold more skeletal muscle NAMPT protein compared to wild type (WT) mice. A concomitant elevation of NMN (5-fold) and NAD+ (3-fold) in NamptTg skeletal muscle revealed increased NAMPT enzymatic activity. WT and NamptTg mice were housed with ('trained') or without ('sedentary') running wheels to elicit voluntary exercise for a period of 7 weeks (WT Sedentary; WT Trained; NamptTg Sedentary; NamptTg Trained). No differences were observed in the proclivity of NamptTg mice to engage in voluntary exercise. Mice were fasted for 5 h prior to sacrifice. Quadriceps muscles were used for the respiration measurements. SUIT protocols were performed in permeabilized fiber bundles using either a glycolytic-derived substrate (pyruvate) or a fatty acid-derived substrate (palmitoyl-carnitine).
NamptTg mice had an increased fatty acid oxidative (FAO) capacity after training (P<0.05; Fig. 1A). Notably, this training-induced improvement in FAO in the NamptTg mice tended to be higher than the trivial increase in FAO flux with training in WT mice (P=0.0595; Fig. 1A). Increased NAMPT levels were sufficient to dramatically improve mitochondrial coupling efficiency, as reflected by the significant reduction in the ratio of proton leak-linked respiration (L) to OXPHOS capacity (P) in the NamptTg mice compared with WT mice at baseline (P<0.05; Figure 1B). While training improved coupling efficiency in the WT mice (P<0.05, Figure 1B), it tended to further improve coupling efficiency in the NamptTg mice as well (P=0.107; Fig. 1B).
Taken together, decreased LEAK/OXPHOS ratios (i.e. improved biochemical coupling efficiency) and an increased capacity to burn fatty acids indicate a synergistic improvement in muscle mitochondrial function via NAMPT and endurance exercise, whereby an increased amount of NAMPT is sufficient to enhance the exercise-induced improvements in substrate metabolism.
• O2k-Network Lab: US FL Orlando Sparks LM
Labels: MiParea: Respiration, mt-Biogenesis;mt-density, Exercise physiology;nutrition;life style
Organism: Mouse
Tissue;cell: Skeletal muscle
Preparation: Permeabilized tissue
Regulation: Coupling efficiency;uncoupling Coupling state: LEAK, OXPHOS
MiP2014: SUIT
Affiliation
1-Translational Research Inst Metabolism Diabetes, Florida Hospital; 2-Sanford Burnham Medical Research Inst; Orlando, FL, USA. - lauren.sparks@flhosp.org
Figure 1
Figure 1. Overexpression of NAMPT improves mitochondrial function after training in skeletal muscle
Respiration was measured in permeabilized muscle fiber bundles using a SUIT protocol with a fatty acid substrate (palmitoyl-carnitine) and targeting both Complex I (CI)- and Complex II (CII)-linked respiration. Respiration is expressed per mtDNA copy number. A: OXPHOS (P) capacities are presented as respiration from combined CI+II+FAO-linked substrates in the presence of adenylates (ADP). B: LEAK (L) respiration was measured in the absence of adenylates (ADP). Coupling control ratios are presented as LEAK divided by OXPHOS capacity on a fatty acid substrate. Bars represent mean±SEM for wild type (WT) sedentary and trained mice and for NAMPT Transgenic (TG) sedentary and trained mice. Letters different from each other indicate statistically significant differences (P<0.05; Tukey’s HSD). N=6 (WT sedentary); N=7 (WT Trained); N=6 (TG sedentary); N=5 (TG trained).
References
- Costford SR, Bajpeyi S, Pasarica M, Albarado DC, Thomas SC, Xie H, Church TS, Jubrias SA, Conley KE, Smith SR (2010) Skeletal muscle NAMPT is induced by exercise in humans. Am J Physiol Endocrinol Metab 298: 117-26.
- Song J, Ke SF, Zhou CC, Zhang SL, Guan YF, Xu TY, Sheng CQ, Wang P, Miao CY (2014) Nicotinamide phosphoribosyltransferase is required for the calorie restriction-mediated improvements in oxidative stress, mitochondrial biogenesis, and metabolic adaptation. J Gerontol A Biol Sci Med Sci 69: 44-57.
