AMP-activated protein kinase regulates nicotinamide phosphoribosyl transferase expression in skeletal muscle

Josef Brandauer; Sara Gry Vienberg; Marianne Agerholm Andersen; Stine Ringholm Jørgensen; Steve Risis; Per Larsen; Jonas Møller Kristensen; Christian Frøsig; Lotte Leick; Joachim Fentz; Sebastian Beck Jørgensen; Bente Kiens; Jørgen Wojtaszewski; Erik Richter; Juleen R Zierath; Laurie J. Goodyear; Henriette Pilegaard; Jonas Thue Treebak

doi:10.1113/jphysiol.2013.259515

AMP-activated protein kinase regulates nicotinamide phosphoribosyl transferase expression in skeletal muscle

Josef Brandauer, Sara Gry Vienberg, Marianne Agerholm Andersen, Stine Ringholm Jørgensen, Steve Risis, Per Larsen, Jonas Møller Kristensen, Christian Frøsig, Lotte Leick, Joachim Fentz, Sebastian Beck Jørgensen, Bente Kiens, Jørgen Wojtaszewski, Erik Richter, Juleen R Zierath, Laurie J. Goodyear, Henriette Pilegaard, Jonas Thue Treebak

59 Citationer (Scopus)

Abstract

Deacetylases such as sirtuins (SIRTs) convert NAD to nicotinamide (NAM). Nicotinamide phosphoribosyl transferase (Nampt) is the rate-limiting enzyme in the NAD salvage pathway responsible for converting NAM to NAD to maintain cellular redox state. Activation of AMP-activated protein kinase (AMPK) increases SIRT activity by elevating NAD levels. As NAM directly inhibits SIRTs, increased Nampt activation or expression could be a metabolic stress response. Evidence suggests that AMPK regulates Nampt mRNA content, but whether repeated AMPK activation is necessary for increasing Nampt protein levels is unknown. To this end, we assessed whether exercise training- or 5-amino-1-β-d-ribofuranosyl-imidazole-4-carboxamide (AICAR)-mediated increases in skeletal muscle Nampt abundance are AMPK dependent. One-legged knee-extensor exercise training in humans increased Nampt protein by 16% (P < 0.05) in the trained, but not the untrained leg. Moreover, increases in Nampt mRNA following acute exercise or AICAR treatment (P < 0.05 for both) were maintained in mouse skeletal muscle lacking a functional AMPK α2 subunit. Nampt protein was reduced in skeletal muscle of sedentary AMPK α2 kinase dead (KD), but 6.5 weeks of endurance exercise training increased skeletal muscle Nampt protein to a similar extent in both wild-type (WT) (24%) and AMPK α2 KD (18%) mice. In contrast, 4 weeks of daily AICAR treatment increased Nampt protein in skeletal muscle in WT mice (27%), but this effect did not occur in AMPK α2 KD mice. In conclusion, functional α2-containing AMPK heterotrimers are required for elevation of skeletal muscle Nampt protein, but not mRNA induction. These findings suggest AMPK plays a post-translational role in the regulation of skeletal muscle Nampt protein abundance, and further indicate that the regulation of cellular energy charge and nutrient sensing is mechanistically related.

Originalsprog	Engelsk
Tidsskrift	Journal of Physiology
Vol/bind	591
Sider (fra-til)	5207-5220
Antal sider	14
ISSN	0022-3751
DOI	https://doi.org/10.1113/jphysiol.2013.259515
Status	Udgivet - okt. 2013

Adgang til dokumentet

10.1113/jphysiol.2013.259515

Citationsformater

Brandauer, J., Vienberg, S. G., Andersen, M. A., Jørgensen, S. R., Risis, S., Larsen, P., Kristensen, J. M., Frøsig, C., Leick, L., Fentz, J., Jørgensen, S. B., Kiens, B., Wojtaszewski, J., Richter, E., Zierath, J. R., Goodyear, L. J., Pilegaard, H., & Treebak, J. T. (2013). AMP-activated protein kinase regulates nicotinamide phosphoribosyl transferase expression in skeletal muscle. Journal of Physiology, 591, 5207-5220. https://doi.org/10.1113/jphysiol.2013.259515

Brandauer, J, Vienberg, SG, Andersen, MA, Jørgensen, SR, Risis, S, Larsen, P, Kristensen, JM, Frøsig, C, Leick, L, Fentz, J, Jørgensen, SB, Kiens, B , Wojtaszewski, J , Richter, E , Zierath, JR, Goodyear, LJ, Pilegaard, H & Treebak, JT 2013, 'AMP-activated protein kinase regulates nicotinamide phosphoribosyl transferase expression in skeletal muscle', Journal of Physiology, bind 591, s. 5207-5220. https://doi.org/10.1113/jphysiol.2013.259515

@article{b275a93b9fbe4748b9fc742c1af8f226,

title = "AMP-activated protein kinase regulates nicotinamide phosphoribosyl transferase expression in skeletal muscle",

abstract = "Deacetylases such as sirtuins (SIRTs) convert NAD to nicotinamide (NAM). Nicotinamide phosphoribosyl transferase (Nampt) is the rate-limiting enzyme in the NAD salvage pathway responsible for converting NAM to NAD to maintain cellular redox state. Activation of AMP-activated protein kinase (AMPK) increases SIRT activity by elevating NAD levels. As NAM directly inhibits SIRTs, increased Nampt activation or expression could be a metabolic stress response. Evidence suggests that AMPK regulates Nampt mRNA content, but whether repeated AMPK activation is necessary for increasing Nampt protein levels is unknown. To this end, we assessed whether exercise training- or 5-amino-1-β-d-ribofuranosyl-imidazole-4-carboxamide (AICAR)-mediated increases in skeletal muscle Nampt abundance are AMPK dependent. One-legged knee-extensor exercise training in humans increased Nampt protein by 16% (P < 0.05) in the trained, but not the untrained leg. Moreover, increases in Nampt mRNA following acute exercise or AICAR treatment (P < 0.05 for both) were maintained in mouse skeletal muscle lacking a functional AMPK α2 subunit. Nampt protein was reduced in skeletal muscle of sedentary AMPK α2 kinase dead (KD), but 6.5 weeks of endurance exercise training increased skeletal muscle Nampt protein to a similar extent in both wild-type (WT) (24%) and AMPK α2 KD (18%) mice. In contrast, 4 weeks of daily AICAR treatment increased Nampt protein in skeletal muscle in WT mice (27%), but this effect did not occur in AMPK α2 KD mice. In conclusion, functional α2-containing AMPK heterotrimers are required for elevation of skeletal muscle Nampt protein, but not mRNA induction. These findings suggest AMPK plays a post-translational role in the regulation of skeletal muscle Nampt protein abundance, and further indicate that the regulation of cellular energy charge and nutrient sensing is mechanistically related.",

author = "Josef Brandauer and Vienberg, {Sara Gry} and Andersen, {Marianne Agerholm} and J{\o}rgensen, {Stine Ringholm} and Steve Risis and Per Larsen and Kristensen, {Jonas M{\o}ller} and Christian Fr{\o}sig and Lotte Leick and Joachim Fentz and J{\o}rgensen, {Sebastian Beck} and Bente Kiens and J{\o}rgen Wojtaszewski and Erik Richter and Zierath, {Juleen R} and Goodyear, {Laurie J.} and Henriette Pilegaard and Treebak, {Jonas Thue}",

note = "CURIS 2013 NEXS 227",

year = "2013",

month = oct,

doi = "10.1113/jphysiol.2013.259515",

language = "English",

volume = "591",

pages = "5207--5220",

journal = "The Journal of Physiology",

issn = "0022-3751",

publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - AMP-activated protein kinase regulates nicotinamide phosphoribosyl transferase expression in skeletal muscle

AU - Brandauer, Josef

AU - Vienberg, Sara Gry

AU - Andersen, Marianne Agerholm

AU - Jørgensen, Stine Ringholm

AU - Risis, Steve

AU - Larsen, Per

AU - Kristensen, Jonas Møller

AU - Frøsig, Christian

AU - Leick, Lotte

AU - Fentz, Joachim

AU - Jørgensen, Sebastian Beck

AU - Kiens, Bente

AU - Wojtaszewski, Jørgen

AU - Richter, Erik

AU - Zierath, Juleen R

AU - Goodyear, Laurie J.

AU - Pilegaard, Henriette

AU - Treebak, Jonas Thue

N1 - CURIS 2013 NEXS 227

PY - 2013/10

Y1 - 2013/10

N2 - Deacetylases such as sirtuins (SIRTs) convert NAD to nicotinamide (NAM). Nicotinamide phosphoribosyl transferase (Nampt) is the rate-limiting enzyme in the NAD salvage pathway responsible for converting NAM to NAD to maintain cellular redox state. Activation of AMP-activated protein kinase (AMPK) increases SIRT activity by elevating NAD levels. As NAM directly inhibits SIRTs, increased Nampt activation or expression could be a metabolic stress response. Evidence suggests that AMPK regulates Nampt mRNA content, but whether repeated AMPK activation is necessary for increasing Nampt protein levels is unknown. To this end, we assessed whether exercise training- or 5-amino-1-β-d-ribofuranosyl-imidazole-4-carboxamide (AICAR)-mediated increases in skeletal muscle Nampt abundance are AMPK dependent. One-legged knee-extensor exercise training in humans increased Nampt protein by 16% (P < 0.05) in the trained, but not the untrained leg. Moreover, increases in Nampt mRNA following acute exercise or AICAR treatment (P < 0.05 for both) were maintained in mouse skeletal muscle lacking a functional AMPK α2 subunit. Nampt protein was reduced in skeletal muscle of sedentary AMPK α2 kinase dead (KD), but 6.5 weeks of endurance exercise training increased skeletal muscle Nampt protein to a similar extent in both wild-type (WT) (24%) and AMPK α2 KD (18%) mice. In contrast, 4 weeks of daily AICAR treatment increased Nampt protein in skeletal muscle in WT mice (27%), but this effect did not occur in AMPK α2 KD mice. In conclusion, functional α2-containing AMPK heterotrimers are required for elevation of skeletal muscle Nampt protein, but not mRNA induction. These findings suggest AMPK plays a post-translational role in the regulation of skeletal muscle Nampt protein abundance, and further indicate that the regulation of cellular energy charge and nutrient sensing is mechanistically related.

AB - Deacetylases such as sirtuins (SIRTs) convert NAD to nicotinamide (NAM). Nicotinamide phosphoribosyl transferase (Nampt) is the rate-limiting enzyme in the NAD salvage pathway responsible for converting NAM to NAD to maintain cellular redox state. Activation of AMP-activated protein kinase (AMPK) increases SIRT activity by elevating NAD levels. As NAM directly inhibits SIRTs, increased Nampt activation or expression could be a metabolic stress response. Evidence suggests that AMPK regulates Nampt mRNA content, but whether repeated AMPK activation is necessary for increasing Nampt protein levels is unknown. To this end, we assessed whether exercise training- or 5-amino-1-β-d-ribofuranosyl-imidazole-4-carboxamide (AICAR)-mediated increases in skeletal muscle Nampt abundance are AMPK dependent. One-legged knee-extensor exercise training in humans increased Nampt protein by 16% (P < 0.05) in the trained, but not the untrained leg. Moreover, increases in Nampt mRNA following acute exercise or AICAR treatment (P < 0.05 for both) were maintained in mouse skeletal muscle lacking a functional AMPK α2 subunit. Nampt protein was reduced in skeletal muscle of sedentary AMPK α2 kinase dead (KD), but 6.5 weeks of endurance exercise training increased skeletal muscle Nampt protein to a similar extent in both wild-type (WT) (24%) and AMPK α2 KD (18%) mice. In contrast, 4 weeks of daily AICAR treatment increased Nampt protein in skeletal muscle in WT mice (27%), but this effect did not occur in AMPK α2 KD mice. In conclusion, functional α2-containing AMPK heterotrimers are required for elevation of skeletal muscle Nampt protein, but not mRNA induction. These findings suggest AMPK plays a post-translational role in the regulation of skeletal muscle Nampt protein abundance, and further indicate that the regulation of cellular energy charge and nutrient sensing is mechanistically related.

U2 - 10.1113/jphysiol.2013.259515

DO - 10.1113/jphysiol.2013.259515

M3 - Journal article

C2 - 23918774

SN - 0022-3751

VL - 591

SP - 5207

EP - 5220

JO - The Journal of Physiology

JF - The Journal of Physiology

ER -

AMP-activated protein kinase regulates nicotinamide phosphoribosyl transferase expression in skeletal muscle

Abstract

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