Inactivation of glycogen synthase kinase-3 beta (GSK-3 beta) enhances skeletal muscle oxidative metabolism

W. F. Theeuwes; H. R. Gosker; R. C. J. Langen; K. J. P. Verhees; N. A. M. Pansters; A. M. W. J. Schols; A. H. V. Remels

doi:10.1016/j.bbadis.2017.09.018

Inactivation of glycogen synthase kinase-3 beta (GSK-3 beta) enhances skeletal muscle oxidative metabolism

W. F. Theeuwes^*, H. R. Gosker, R. C. J. Langen, K. J. P. Verhees, N. A. M. Pansters, A. M. W. J. Schols, A. H. V. Remels

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Background: Aberrant skeletal muscle mitochondrial oxidative metabolism is a debilitating feature of chronic diseases such as chronic obstructive pulmonary disease, type 2 diabetes and chronic heart failure. Evidence in non-muscle cells suggests that glycogen synthase kinase-3 beta (GSK-3 beta) represses mitochondrial biogenesis and inhibits PPAR-gamma co-activator 1 (PGC-1), a master regulator of cellular oxidative metabolism. The role of GSK-3 beta in the regulation of skeletal muscle oxidative metabolism is unknown.

Aims: We hypothesized that inactivation of GSK-3 beta stimulates muscle oxidative metabolism by activating PGC-1 signaling and explored if GSK-3 beta inactivation could protect against physical inactivity-induced alterations in skeletal muscle oxidative metabolism.

Methods: GSK-3 beta was modulated genetically and pharmacologically in C2C12 myotubes in vitro and in skeletal muscle in vivo. Wild-type and muscle-specific GSK-3 beta knock-out (KO) mice were subjected to hind limb suspension for 14 days. Key constituents of oxidative metabolism and PGC-1. signaling were investigated.

Results: In vitro, knock-down of GSK-3 beta increased mitochondrial DNA copy number, protein and mRNA abundance of oxidative phosphorylation (OXPHOS) complexes and activity of oxidative metabolic enzymes but also enhanced protein and mRNA abundance of key PGC-1 signaling constituents. Similarly, pharmacological inhibition of GSK-3 beta increased transcript and protein abundance of key constituents and regulators of mitochondrial energy metabolism. Furthermore, GSK-3 beta KO animals were protected against unloading-induced decrements in expression levels of these constituents.

Conclusion: Inactivation of GSK-3 beta up-regulates skeletal muscle mitochondrial metabolism and increases expression levels of PGC-1 signaling constituents. In vivo, GSK-3 beta KO protects against inactivity-induced reductions in muscle metabolic gene expression.

Original language	English
Pages (from-to)	3075-3086
Number of pages	12
Journal	Biochimica et Biophysica Acta-Molecular Basis of Disease
Volume	1863
Issue number	12
DOIs	https://doi.org/10.1016/j.bbadis.2017.09.018
Publication status	Published - Dec 2017

Keywords

GSK-3 beta
Mitochondrial biogenesis
Mitochondrial metabolism
Skeletal muscle
Hind limb suspension
PGC-1 alpha
IMPROVES MITOCHONDRIAL-FUNCTION
ALPHA ERR-ALPHA
MYOGENIC DIFFERENTIATION
GENE-EXPRESSION
SIGNALING PATHWAYS
INSULIN-RESISTANCE
ENERGY-METABOLISM
COACTIVATOR PGC-1
RECEPTOR-GAMMA
KEY REGULATOR

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10.1016/j.bbadis.2017.09.018

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Cite this

@article{c032277faa9d46d88dcc4f2a32bfb65e,

title = "Inactivation of glycogen synthase kinase-3 beta (GSK-3 beta) enhances skeletal muscle oxidative metabolism",

abstract = "Background: Aberrant skeletal muscle mitochondrial oxidative metabolism is a debilitating feature of chronic diseases such as chronic obstructive pulmonary disease, type 2 diabetes and chronic heart failure. Evidence in non-muscle cells suggests that glycogen synthase kinase-3 beta (GSK-3 beta) represses mitochondrial biogenesis and inhibits PPAR-gamma co-activator 1 (PGC-1), a master regulator of cellular oxidative metabolism. The role of GSK-3 beta in the regulation of skeletal muscle oxidative metabolism is unknown.Aims: We hypothesized that inactivation of GSK-3 beta stimulates muscle oxidative metabolism by activating PGC-1 signaling and explored if GSK-3 beta inactivation could protect against physical inactivity-induced alterations in skeletal muscle oxidative metabolism.Methods: GSK-3 beta was modulated genetically and pharmacologically in C2C12 myotubes in vitro and in skeletal muscle in vivo. Wild-type and muscle-specific GSK-3 beta knock-out (KO) mice were subjected to hind limb suspension for 14 days. Key constituents of oxidative metabolism and PGC-1. signaling were investigated.Results: In vitro, knock-down of GSK-3 beta increased mitochondrial DNA copy number, protein and mRNA abundance of oxidative phosphorylation (OXPHOS) complexes and activity of oxidative metabolic enzymes but also enhanced protein and mRNA abundance of key PGC-1 signaling constituents. Similarly, pharmacological inhibition of GSK-3 beta increased transcript and protein abundance of key constituents and regulators of mitochondrial energy metabolism. Furthermore, GSK-3 beta KO animals were protected against unloading-induced decrements in expression levels of these constituents.Conclusion: Inactivation of GSK-3 beta up-regulates skeletal muscle mitochondrial metabolism and increases expression levels of PGC-1 signaling constituents. In vivo, GSK-3 beta KO protects against inactivity-induced reductions in muscle metabolic gene expression.",

keywords = "GSK-3 beta, Mitochondrial biogenesis, Mitochondrial metabolism, Skeletal muscle, Hind limb suspension, PGC-1 alpha, IMPROVES MITOCHONDRIAL-FUNCTION, ALPHA ERR-ALPHA, MYOGENIC DIFFERENTIATION, GENE-EXPRESSION, SIGNALING PATHWAYS, INSULIN-RESISTANCE, ENERGY-METABOLISM, COACTIVATOR PGC-1, RECEPTOR-GAMMA, KEY REGULATOR",

author = "Theeuwes, {W. F.} and Gosker, {H. R.} and Langen, {R. C. J.} and Verhees, {K. J. P.} and Pansters, {N. A. M.} and Schols, {A. M. W. J.} and Remels, {A. H. V.}",

year = "2017",

month = dec,

doi = "10.1016/j.bbadis.2017.09.018",

language = "English",

volume = "1863",

pages = "3075--3086",

journal = "Biochimica et Biophysica Acta-Molecular Basis of Disease",

issn = "0925-4439",

publisher = "Elsevier Science",

number = "12",

}

Inactivation of glycogen synthase kinase-3 beta (GSK-3 beta) enhances skeletal muscle oxidative metabolism. / Theeuwes, W. F.; Gosker, H. R.; Langen, R. C. J.; Verhees, K. J. P.; Pansters, N. A. M.; Schols, A. M. W. J.; Remels, A. H. V.

In: Biochimica et Biophysica Acta-Molecular Basis of Disease, Vol. 1863, No. 12, 12.2017, p. 3075-3086.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Inactivation of glycogen synthase kinase-3 beta (GSK-3 beta) enhances skeletal muscle oxidative metabolism

AU - Theeuwes, W. F.

AU - Gosker, H. R.

AU - Langen, R. C. J.

AU - Verhees, K. J. P.

AU - Pansters, N. A. M.

AU - Schols, A. M. W. J.

AU - Remels, A. H. V.

PY - 2017/12

Y1 - 2017/12

N2 - Background: Aberrant skeletal muscle mitochondrial oxidative metabolism is a debilitating feature of chronic diseases such as chronic obstructive pulmonary disease, type 2 diabetes and chronic heart failure. Evidence in non-muscle cells suggests that glycogen synthase kinase-3 beta (GSK-3 beta) represses mitochondrial biogenesis and inhibits PPAR-gamma co-activator 1 (PGC-1), a master regulator of cellular oxidative metabolism. The role of GSK-3 beta in the regulation of skeletal muscle oxidative metabolism is unknown.Aims: We hypothesized that inactivation of GSK-3 beta stimulates muscle oxidative metabolism by activating PGC-1 signaling and explored if GSK-3 beta inactivation could protect against physical inactivity-induced alterations in skeletal muscle oxidative metabolism.Methods: GSK-3 beta was modulated genetically and pharmacologically in C2C12 myotubes in vitro and in skeletal muscle in vivo. Wild-type and muscle-specific GSK-3 beta knock-out (KO) mice were subjected to hind limb suspension for 14 days. Key constituents of oxidative metabolism and PGC-1. signaling were investigated.Results: In vitro, knock-down of GSK-3 beta increased mitochondrial DNA copy number, protein and mRNA abundance of oxidative phosphorylation (OXPHOS) complexes and activity of oxidative metabolic enzymes but also enhanced protein and mRNA abundance of key PGC-1 signaling constituents. Similarly, pharmacological inhibition of GSK-3 beta increased transcript and protein abundance of key constituents and regulators of mitochondrial energy metabolism. Furthermore, GSK-3 beta KO animals were protected against unloading-induced decrements in expression levels of these constituents.Conclusion: Inactivation of GSK-3 beta up-regulates skeletal muscle mitochondrial metabolism and increases expression levels of PGC-1 signaling constituents. In vivo, GSK-3 beta KO protects against inactivity-induced reductions in muscle metabolic gene expression.

AB - Background: Aberrant skeletal muscle mitochondrial oxidative metabolism is a debilitating feature of chronic diseases such as chronic obstructive pulmonary disease, type 2 diabetes and chronic heart failure. Evidence in non-muscle cells suggests that glycogen synthase kinase-3 beta (GSK-3 beta) represses mitochondrial biogenesis and inhibits PPAR-gamma co-activator 1 (PGC-1), a master regulator of cellular oxidative metabolism. The role of GSK-3 beta in the regulation of skeletal muscle oxidative metabolism is unknown.Aims: We hypothesized that inactivation of GSK-3 beta stimulates muscle oxidative metabolism by activating PGC-1 signaling and explored if GSK-3 beta inactivation could protect against physical inactivity-induced alterations in skeletal muscle oxidative metabolism.Methods: GSK-3 beta was modulated genetically and pharmacologically in C2C12 myotubes in vitro and in skeletal muscle in vivo. Wild-type and muscle-specific GSK-3 beta knock-out (KO) mice were subjected to hind limb suspension for 14 days. Key constituents of oxidative metabolism and PGC-1. signaling were investigated.Results: In vitro, knock-down of GSK-3 beta increased mitochondrial DNA copy number, protein and mRNA abundance of oxidative phosphorylation (OXPHOS) complexes and activity of oxidative metabolic enzymes but also enhanced protein and mRNA abundance of key PGC-1 signaling constituents. Similarly, pharmacological inhibition of GSK-3 beta increased transcript and protein abundance of key constituents and regulators of mitochondrial energy metabolism. Furthermore, GSK-3 beta KO animals were protected against unloading-induced decrements in expression levels of these constituents.Conclusion: Inactivation of GSK-3 beta up-regulates skeletal muscle mitochondrial metabolism and increases expression levels of PGC-1 signaling constituents. In vivo, GSK-3 beta KO protects against inactivity-induced reductions in muscle metabolic gene expression.

KW - GSK-3 beta

KW - Mitochondrial biogenesis

KW - Mitochondrial metabolism

KW - Skeletal muscle

KW - Hind limb suspension

KW - PGC-1 alpha

KW - IMPROVES MITOCHONDRIAL-FUNCTION

KW - ALPHA ERR-ALPHA

KW - MYOGENIC DIFFERENTIATION

KW - GENE-EXPRESSION

KW - SIGNALING PATHWAYS

KW - INSULIN-RESISTANCE

KW - ENERGY-METABOLISM

KW - COACTIVATOR PGC-1

KW - RECEPTOR-GAMMA

KW - KEY REGULATOR

U2 - 10.1016/j.bbadis.2017.09.018

DO - 10.1016/j.bbadis.2017.09.018

M3 - Article

C2 - 28943449

VL - 1863

SP - 3075

EP - 3086

JO - Biochimica et Biophysica Acta-Molecular Basis of Disease

JF - Biochimica et Biophysica Acta-Molecular Basis of Disease

SN - 0925-4439

IS - 12

ER -