Activation of Wnt/beta-catenin signaling increases insulin sensitivity through a reciprocal regulation of Wnt10b and SREBP-1c in skeletal muscle cells.
BACKGROUND
Intramyocellular lipid accumulation is strongly related to insulin resistance in humans, and we have shown that high glucose concentration induced de novo lipogenesis and insulin resistance in murin muscle cells. Alterations in Wnt signaling impact the balance between myogenic and adipogenic programs in myoblasts, partly due to the decrease of Wnt10b protein. As recent studies point towards a role for Wnt signaling in the pathogenesis of type 2 diabetes, we hypothesized that activation of Wnt signaling could play a crucial role in muscle insulin sensitivity.


RESULTS
Here we demonstrate that SREBP-1c and Wnt10b display inverse expression patterns during muscle ontogenesis and regeneration, as well as during satellite cells differentiation. The Wnt/beta-catenin pathway was reactivated in contracting myotubes using siRNA mediated SREBP-1 knockdown, Wnt10b over-expression or inhibition of GSK-3beta, whereas Wnt signaling was inhibited in myoblasts through silencing of Wnt10b. SREBP-1 knockdown was sufficient to induce Wnt10b protein expression in contracting myotubes and to activate the Wnt/beta-catenin pathway. Conversely, silencing Wnt10b in myoblasts induced SREBP-1c protein expression, suggesting a reciprocal regulation. Stimulation of the Wnt/beta-catenin pathway i) drastically decreased SREBP-1c protein and intramyocellular lipid deposition in myotubes; ii) increased basal glucose transport in both insulin-sensitive and insulin-resistant myotubes through a differential activation of Akt and AMPK pathways; iii) restored insulin sensitivity in insulin-resistant myotubes.


CONCLUSIONS
We conclude that activation of Wnt/beta-catenin signaling in skeletal muscle cells improved insulin sensitivity by i) decreasing intramyocellular lipid deposition through downregulation of SREBP-1c; ii) increasing insulin effects through a differential activation of the Akt/PKB and AMPK pathways; iii) inhibiting the MAPK pathway. A crosstalk between these pathways and Wnt/beta-catenin signaling in skeletal muscle opens the exciting possibility that organ-selective modulation of Wnt signaling might become an attractive therapeutic target in regenerative medicine and to treat obese and diabetic populations.
Abiola
Mounira
M
Genetics and Development Department, Institut Cochin, Université Paris Descartes, CNRS UMR 8104, Paris, France.
Favier
Maryline
M
Christodoulou-Vafeiadou
Eleni
E
Pichard
Anne-Lise
AL
Martelly
Isabelle
I
Guillet-Deniau
Isabelle
I
D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D032496:Satellite Cells, Skeletal Muscle / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
C483321:6-bromoindirubin-3'-oxime; D051275:Glucose Transporter Type 4; D007211:Indoles; D007328:Insulin; D010091:Oximes; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D051153:Wnt Proteins; C102068:Wnt10b protein, mouse; D051176:beta Catenin; D003847:Deoxyglucose; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D000263:Adenylate Kinase; D005947:Glucose