Abstract
Mice overexpressing NAMPT in skeletal muscle (NamptTg mice) develop higher exercise endurance and maximal aerobic capacity (VO2max) following voluntary exercise training compared to wild-type (WT) mice. Here, we aimed to investigate the mechanisms underlying by determining skeletal muscle mitochondrial respiratory capacity in NamptTg and WT mice. Body weight and body composition, tissue weight (gastrocnemius, quadriceps, soleus, heart, liver, and epididymal white adipose tissue), skeletal muscle and liver glycogen content, VO2max, skeletal muscle mitochondrial respiratory capacity (measured by high-resolution respirometry), skeletal muscle gene expression (measured by microarray and qPCR), and skeletal muscle protein content (measured by Western blot) were determined following 6 weeks of voluntary exercise training (access to running wheel) in 13-week-old male NamptTg (exercised NamptTg) mice and WT (exercised WT) mice. Daily running distance and running time during the voluntary exercise training protocol were recorded. Daily running distance (p = 0.51) and running time (p = 0.85) were not significantly different between exercised NamptTg mice and exercised WT mice. VO2max was higher in exercised NamptTg mice compared to exercised WT mice (p = 0.02). Body weight (p = 0.92), fat mass (p = 0.49), lean mass (p = 0.91), tissue weight (all p > 0.05), and skeletal muscle (p = 0.72) and liver (p = 0.94) glycogen content were not significantly different between exercised NamptTg mice and exercised WT mice. Complex I oxidative phosphorylation (OXPHOS) respiratory capacity supported by fatty acid substrates (p < 0.01), maximal (complex I+II) OXPHOS respiratory capacity supported by glycolytic (p = 0.02) and fatty acid (p < 0.01) substrates, and maximal uncoupled respiratory capacity supported by fatty acid substrates (p < 0.01) was higher in exercised NamptTg mice compared to exercised WT mice. Transcriptomic analyses revealed differential expression for genes involved in oxidative metabolism in exercised NamptTg mice compared to exercised WT mice, specifically, enrichment for the gene set related to the SIRT3-mediated signaling pathway. SIRT3 protein content correlated with NAMPT protein content (r = 0.61, p = 0.04). In conclusion, NamptTg mice develop higher exercise capacity following voluntary exercise training compared to WT mice, which is paralleled by higher mitochondrial respiratory capacity in skeletal muscle. The changes in SIRT3 targets suggest that these effects are due to remodeling of mitochondrial function.
Highlights
Nicotinamide phosphoribosyl transferase (NAMPT), a homodimeric type II phosphoribosyl transferase, is the rate-limiting enzyme in the salvage pathway that produces nicotinamide adenine dinucleotide (NAD+) (Wang et al, 2006; Hirschey et al, 2011; Fletcher et al, 2017)
We recently showed that mice overexpressing NAMPT in skeletal muscle (NamptTg mice) increased their exercise endurance by threefold and developed higher exercise endurance and maximal aerobic capacity (VO2max) in comparison to wild-type (WT) mice following 7 weeks of voluntary exercise training (Costford et al, 2017)
We previously showed that a 10-fold higher NAMPT protein content and 7-fold higher NAMPT enzyme activity in skeletal muscle of NamptTg mice when compared to WT mice increased skeletal muscle NAD+ levels by 1.6-fold (Costford et al, 2017)
Summary
Nicotinamide phosphoribosyl transferase (NAMPT), a homodimeric type II phosphoribosyl transferase, is the rate-limiting enzyme in the salvage pathway that produces nicotinamide adenine dinucleotide (NAD+) (Wang et al, 2006; Hirschey et al, 2011; Fletcher et al, 2017). NAMPT protein content in skeletal muscle was found to be twofold higher in trained individuals in comparison to sedentary individuals (Costford et al, 2010). NAMPT protein content in skeletal muscle of inactive individuals increased profoundly following 3 weeks of exercise training (Costford et al, 2010). We recently showed that mice overexpressing NAMPT in skeletal muscle (NamptTg mice) increased their exercise endurance by threefold and developed higher exercise endurance and maximal aerobic capacity (VO2max) in comparison to wild-type (WT) mice following 7 weeks of voluntary exercise training (Costford et al, 2017). The observation that elevated NAMPT in skeletal muscle resulted in a striking improvement in exercise endurance and VO2max when combined with exercise training, but not when no exercise training was performed, revealed a close interaction between skeletal muscle NAMPT and the effect of exercise training on exercise performance, but the underlying mechanism remains unknown
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