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Suppression of 5 '-...
Suppression of 5 '-Nucleotidase Enzymes Promotes AMP-activated Protein Kinase (AMPK) Phosphorylation and Metabolism in Human and Mouse Skeletal Muscle
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- Kulkarni, Sameer S. (author)
- Karolinska Institutet, Stockholm, Sweden
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- Karlsson, Håkan K. R. (author)
- Karolinska Institutet,Karolinska Institutet, Stockholm, Sweden
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- Szekeres, Ferenc (author)
- Karolinska Institutet,Karolinska Institutet, Stockholm, Sweden
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- Chibalin, Alexander V. (author)
- Karolinska Institutet,Karolinska Institutet, Stockholm, Sweden
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- Krook, Anna (author)
- Karolinska Institutet, Stockholm, Sweden
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- Zierath, Juleen R. (author)
- Karolinska Institutet,Karolinska Institutet, Stockholm, Sweden
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(creator_code:org_t)
- American Society for Biochemistry and Molecular Biology, Inc. 2011
- 2011
- English.
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In: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology, Inc.. - 0021-9258 .- 1083-351X. ; 286:40, s. 34567-34574
- Related links:
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- The 5'-nucleotidase (NT5) family of enzyme dephosphorylates non-cyclic nucleoside monophosphates to produce nucleosides and inorganic phosphates. We hypothesized that gene silencing of NT5 enzymes to increase the intracellular availability of AMP would increase AMP-activated protein kinase (AMPK) activity and metabolism. We determined the role of cytosolic NT5 in metabolic responses linked to the development of insulin resistance in obesity and type 2 diabetes. Using siRNA to silence NT5C2 expression in cultured human myotubes, we observed a 2-fold increase in the AMP/ATP ratio, a 2.4-fold increase in AMPK phosphorylation (Thr(172)), and a 2.8-fold increase in acetyl-CoA carboxylase phosphorylation (Ser(79)) (p<0.05). siRNA silencing of NT5C2 expression increased palmitate oxidation by 2-fold in the absence and by 8-fold in the presence of 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside. This was paralleled by an increase in glucose transport and a decrease in glucose oxidation, incorporation into glycogen, and lactate release from NT5C2-depleted myotubes. Gene silencing of NT5C1A by shRNA injection and electroporation in mouse tibialis anterior muscle reduced protein content (60%; p<0.05) and increased phosphorylation of AMPK (60%; p<0.05) and acetyl-CoA carboxylase (50%; p<0.05) and glucose uptake (20%; p<0.05). Endogenous expression of NT5C enzymes inhibited basal lipid oxidation and glucose transport in skeletal muscle. Reduction of 5'-nucleotidase expression or activity may promote metabolic flexibility in type 2 diabetes.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Physiology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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