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RESEARCH ARTICLE

Skeletal Muscle NAMPT is Induced by Exercise in Humans

¹Pennington Biomedical Research Center ²University of Washington ³University of Washington Medical Center

Submitted 15 May 2009 ; revised 2 November 2009 ; accepted in final form 2 November 2009

In mammals, nicotinamide phosphoribosyltransferase (NAMPT) is responsible for the first and rate-limiting step in the conversion of nicotinamide to nicotinamide adenine dinucleotide (NAD⁺). NAD⁺ is an obligate co-substrate for mammalian sirtuin 1 (SIRT1), a deacetylase which activates peroxisome proliferator-activated receptor coactivator-1 (PGC-1), which in turn can activate mitochondrial biogenesis. Given that mitochondrial biogenesis is activated by exercise, we hypothesized that exercise would increase NAMPT expression, as a potential mechanism leading to increased mitochondrial content in muscle. A cross-sectional analysis of human subjects showed that athletes had ~2-fold higher skeletal muscle NAMPT protein expression compared to sedentary obese, non-obese and type 2 diabetic subjects (P < 0.05). NAMPT protein correlated with mitochondrial content as estimated by complex III protein content (R² = 0.28, P < 0.01), MRS-measured maximal ATP synthesis (R² = 0.37, P = 0.002), and VO₂max (R² = 0.63, P < 0.0001). In an exercise intervention study, NAMPT protein increased by 127% in sedentary non-obese subjects after 3 weeks of exercise training (P < 0.01). Treatment of primary human myotubes with forskolin, a cAMP signaling pathway activator, resulted in a ~2.5-fold increase in NAMPT protein expression, whereas treatment with ionomycin had no effect. Activation of AMPK via AICAR resulted in a ~3.4-fold increase in NAMPT mRNA (P < 0.05) as well as modest increases in NAMPT protein (P < 0.05) and mitochondrial content (P < 0.05). These results demonstrate that exercise increases skeletal muscle NAMPT expression and that NAMPT correlates with mitochondrial content. Further studies are necessary to elucidate the pathways regulating NAMPT as well as its downstream effects.

PBEF; visfatin; mitochondria; AMPK