Skeletal muscle overexpression of nicotinamide phosphoribosyl transferase in mice coupled with voluntary exercise augments exercise endurance

Abstract

ObjectiveNicotinamide phosphoribosyl transferase (NAMPT) is the rate-limiting enzyme in the salvage pathway that produces nicotinamide adenine dinucleotide (NAD+), an essential co-substrate regulating a myriad of signaling pathways. We produced a mouse that overexpressed NAMPT in skeletal muscle (NamptTg) and hypothesized that NamptTg mice would have increased oxidative capacity, endurance performance, and mitochondrial gene expression, and would be rescued from metabolic abnormalities that developed with high fat diet (HFD) feeding.MethodsInsulin sensitivity (hyperinsulinemic-euglycemic clamp) was assessed in NamptTg and WT mice fed very high fat diet (VHFD, 60% by kcal) or chow diet (CD). The aerobic capacity (VO2max) and endurance performance of NamptTg and WT mice before and after 7 weeks of voluntary exercise training (running wheel in home cage) or sedentary conditions (no running wheel) were measured. Skeletal muscle mitochondrial gene expression was also measured in exercised and sedentary mice and in mice fed HFD (45% by kcal) or low fat diet (LFD, 10% by kcal).ResultsNAMPT enzyme activity in skeletal muscle was 7-fold higher in NamptTg mice versus WT mice. There was a concomitant 1.6-fold elevation of skeletal muscle NAD+. NamptTg mice fed VHFD were partially protected against body weight gain, but not against insulin resistance. Notably, voluntary exercise training elicited a 3-fold higher exercise endurance in NamptTg versus WT mice. Mitochondrial gene expression was higher in NamptTg mice compared to WT mice, especially when fed HFD. Mitochondrial gene expression was higher in exercised NamptTg mice than in sedentary WT mice.ConclusionsOur studies have unveiled a fascinating interaction between elevated NAMPT activity in skeletal muscle and voluntary exercise that was manifest as a striking improvement in exercise endurance.

Administration of Nicotinamide Mononucleotide (NMN) Reduces Metabolic Impairment in Male Mouse Offspring from Obese Mothers

“…Recently Dall and colleagues reported that the NAD + salvage pathway is unaffected by prolonged HFD consumption [40]. Another study with skeletal muscle overexpression of a rate limiting enzyme of the NAD + salvage pathway resulted in increased muscle NAD + concentration and exercise endurance [41]. Therefore, as we expect that the changes in liver triglycerides are driven by increased NAD + in that organ [18] it is attractive to hypothesise that the NAD + salvage pathway is reduced by maternal obesity and can be ameliorated by the administration of NMN.…”

Sarcolipin Signaling Promotes Mitochondrial Biogenesis and Oxidative Metabolism in Skeletal Muscle

“…Glucose clamping was done as previously described ( Ayala et al, 2007 , 2011 ; Costford et al, 2018 ).…”

A new protein curbs the hypertrophic effect of myostatin inhibition, adding remarkable endurance to motor performance in mice

“…This strongly indicates that to induce long-term sustaining muscle activity, the activin receptor inhibitor and the neuronal agrin fragment need to be present on one molecule, as no enhancement of the motor performance was observed when the parts of the molecules were administered separately. To the best of our knowledge, only one recent report [32] describes the successful enhancement of endurance in motor performance. There are, however, important differences to the current study.…”