Post-transcriptional gene silencing of ribosomal protein S6 kinase 1 restores insulin action in leucine-treated skeletal muscle

TY - JOUR

T1 - Post-transcriptional gene silencing of ribosomal protein S6 kinase 1 restores insulin action in leucine-treated skeletal muscle

AU - Deshmukh, Atul

AU - Salehzadeh, F

AU - Metayer-Coustard, S

AU - Fahlman, R

AU - Nair, K S

AU - Al-Khalili, L

PY - 2009/4

Y1 - 2009/4

N2 - Excessive nutrients, especially amino acids, impair insulin action on glucose metabolism in skeletal muscle. We tested the hypothesis that the branched-chain amino acid leucine reduces acute insulin action in primary myotubes via a negative feedback mechanism involving ribosomal protein S6 kinase 1 (S6K1). The effect of S6K1 on glucose metabolism was determined by applying RNA interference (siRNA). Leucine (5 mM) reduced glucose uptake and incorporation to glycogen by 13% and 22%, respectively, compared to the scramble siRNA-transfected control at the basal level. Leucine also reduced insulin-stimulated Akt phosphorylation, glucose uptake and glucose incorporation to glycogen (39%, 39% and 37%, respectively), and this reduction was restored after S6K1 silencing. Depletion of S6K1 enhanced basal glucose utilization and protected against the development of impaired insulin action, in response to excessive leucine. In conclusion, S6K1 plays an important role in the regulation of insulin action on glucose metabolism in skeletal muscle.

AB - Excessive nutrients, especially amino acids, impair insulin action on glucose metabolism in skeletal muscle. We tested the hypothesis that the branched-chain amino acid leucine reduces acute insulin action in primary myotubes via a negative feedback mechanism involving ribosomal protein S6 kinase 1 (S6K1). The effect of S6K1 on glucose metabolism was determined by applying RNA interference (siRNA). Leucine (5 mM) reduced glucose uptake and incorporation to glycogen by 13% and 22%, respectively, compared to the scramble siRNA-transfected control at the basal level. Leucine also reduced insulin-stimulated Akt phosphorylation, glucose uptake and glucose incorporation to glycogen (39%, 39% and 37%, respectively), and this reduction was restored after S6K1 silencing. Depletion of S6K1 enhanced basal glucose utilization and protected against the development of impaired insulin action, in response to excessive leucine. In conclusion, S6K1 plays an important role in the regulation of insulin action on glucose metabolism in skeletal muscle.

KW - Female

KW - Glucose

KW - Glycogen

KW - Humans

KW - Insulin

KW - Leucine

KW - Male

KW - Middle Aged

KW - Muscle, Skeletal

KW - RNA Interference

KW - RNA, Small Interfering

KW - Ribosomal Protein S6 Kinases, 70-kDa

KW - Ribosomal Proteins

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1007/s00018-009-8818-y

DO - 10.1007/s00018-009-8818-y

M3 - Journal article

C2 - 19266162

SN - 1420-682X

VL - 66

SP - 1457

EP - 1466

JO - Cellular and molecular life sciences : CMLS

JF - Cellular and molecular life sciences : CMLS

IS - 8

ER -