Inactivation of glycogen synthase kinase 3 beta (GSK-3 beta) enhances mitochondrial biogenesis during myogenesis

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

doi:10.1016/j.bbadis.2018.06.002

Inactivation of glycogen synthase kinase 3 beta (GSK-3 beta) enhances mitochondrial biogenesis during myogenesis

W. F. Theeuwes, H. R. Gosker^*, R. C. J. Langen, 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

Abstract

Background: Mitochondria] biogenesis is crucial for myogenic differentiation and regeneration of skeletal muscle tissue and is tightly controlled by the peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC-1) signaling network. In the present study, we hypothesized that inactivation of glycogen synthase kinase (GSK)-3 beta, previously suggested to interfere with PGC-1 in non-muscle cells, potentiates PGC-1 signaling and the development of mitochondrial biogenesis during myogenesis, ultimately resulting in an enhanced myotube oxidative capacity.

Methods: GSK-3 beta was inactivated genetically or pharmacologically during myogenic differentiation of C2C12 muscle cells. In addition, m. gastrocnemius tissue was collected from wild-type and muscle-specific GSK-3 beta knockout (KO) mice at different time-points during the reloading/regeneration phase following a 14-day hind-limb suspension period. Subsequently, expression levels of constituents of the PGC-1 signaling network as well as key parameters of mitochondrial oxidative metabolism were investigated.

Results: In vitro, both knock-down as well as pharmacological inhibition of GSK-3 beta not only increased expression levels of important constituents of the PGC-1 signaling network, but also potentiated myogenic differentiation associated increases in mitochondrial respiration, mitochondrial DNA copy number, oxidative phosphorylation (OXPHOS) protein abundance and the activity of key enzymes involved in the Krebs cycle and fatty acid beta-oxidation. In addition, GSK-3 beta KO animals showed augmented reloading-induced increases in skeletal muscle gene expression of constituents of the PGC-1 signaling network as well as sub-units of OXPHOS complexes compared to wild-type animals.

Conclusion: Inactivation of GSK-3 beta stimulates activation of PGC-1 signaling and mitochondrial biogenesis during myogenic differentiation and reloading of the skeletal musculature.

Original language	English
Pages (from-to)	2913-2926
Number of pages	14
Journal	Biochimica et Biophysica Acta-Molecular Basis of Disease
Volume	1864
Issue number	9
DOIs	https://doi.org/10.1016/j.bbadis.2018.06.002
Publication status	Published - Sept 2018

Keywords

GSK-3 beta
Myogenic differentiation
Myogenesis
PGC-1 and mitochondrial biogenesis
PROLIFERATOR-ACTIVATED RECEPTOR
ADULT SKELETAL-MUSCLE
OBSTRUCTIVE PULMONARY-DISEASE
PDK4 GENE-EXPRESSION
ERR-ALPHA
OXIDATIVE CAPACITY
SATELLITE CELLS
HEART-FAILURE
MYOBLAST DIFFERENTIATION
TRANSCRIPTIONAL CONTROL

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@article{1eed4a2503774ac2ac87f144968bf133,

title = "Inactivation of glycogen synthase kinase 3 beta (GSK-3 beta) enhances mitochondrial biogenesis during myogenesis",

abstract = "Background: Mitochondria] biogenesis is crucial for myogenic differentiation and regeneration of skeletal muscle tissue and is tightly controlled by the peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC-1) signaling network. In the present study, we hypothesized that inactivation of glycogen synthase kinase (GSK)-3 beta, previously suggested to interfere with PGC-1 in non-muscle cells, potentiates PGC-1 signaling and the development of mitochondrial biogenesis during myogenesis, ultimately resulting in an enhanced myotube oxidative capacity.Methods: GSK-3 beta was inactivated genetically or pharmacologically during myogenic differentiation of C2C12 muscle cells. In addition, m. gastrocnemius tissue was collected from wild-type and muscle-specific GSK-3 beta knockout (KO) mice at different time-points during the reloading/regeneration phase following a 14-day hind-limb suspension period. Subsequently, expression levels of constituents of the PGC-1 signaling network as well as key parameters of mitochondrial oxidative metabolism were investigated.Results: In vitro, both knock-down as well as pharmacological inhibition of GSK-3 beta not only increased expression levels of important constituents of the PGC-1 signaling network, but also potentiated myogenic differentiation associated increases in mitochondrial respiration, mitochondrial DNA copy number, oxidative phosphorylation (OXPHOS) protein abundance and the activity of key enzymes involved in the Krebs cycle and fatty acid beta-oxidation. In addition, GSK-3 beta KO animals showed augmented reloading-induced increases in skeletal muscle gene expression of constituents of the PGC-1 signaling network as well as sub-units of OXPHOS complexes compared to wild-type animals.Conclusion: Inactivation of GSK-3 beta stimulates activation of PGC-1 signaling and mitochondrial biogenesis during myogenic differentiation and reloading of the skeletal musculature.",

keywords = "GSK-3 beta, Myogenic differentiation, Myogenesis, PGC-1 and mitochondrial biogenesis, PROLIFERATOR-ACTIVATED RECEPTOR, ADULT SKELETAL-MUSCLE, OBSTRUCTIVE PULMONARY-DISEASE, PDK4 GENE-EXPRESSION, ERR-ALPHA, OXIDATIVE CAPACITY, SATELLITE CELLS, HEART-FAILURE, MYOBLAST DIFFERENTIATION, TRANSCRIPTIONAL CONTROL",

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

year = "2018",

month = sep,

doi = "10.1016/j.bbadis.2018.06.002",

language = "English",

volume = "1864",

pages = "2913--2926",

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

issn = "0925-4439",

publisher = "Elsevier B.V.",

number = "9",

}

TY - JOUR

T1 - Inactivation of glycogen synthase kinase 3 beta (GSK-3 beta) enhances mitochondrial biogenesis during myogenesis

AU - Theeuwes, W. F.

AU - Gosker, H. R.

AU - Langen, R. C. J.

AU - Pansters, N. A. M.

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

AU - Remels, A. H. V.

PY - 2018/9

Y1 - 2018/9

N2 - Background: Mitochondria] biogenesis is crucial for myogenic differentiation and regeneration of skeletal muscle tissue and is tightly controlled by the peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC-1) signaling network. In the present study, we hypothesized that inactivation of glycogen synthase kinase (GSK)-3 beta, previously suggested to interfere with PGC-1 in non-muscle cells, potentiates PGC-1 signaling and the development of mitochondrial biogenesis during myogenesis, ultimately resulting in an enhanced myotube oxidative capacity.Methods: GSK-3 beta was inactivated genetically or pharmacologically during myogenic differentiation of C2C12 muscle cells. In addition, m. gastrocnemius tissue was collected from wild-type and muscle-specific GSK-3 beta knockout (KO) mice at different time-points during the reloading/regeneration phase following a 14-day hind-limb suspension period. Subsequently, expression levels of constituents of the PGC-1 signaling network as well as key parameters of mitochondrial oxidative metabolism were investigated.Results: In vitro, both knock-down as well as pharmacological inhibition of GSK-3 beta not only increased expression levels of important constituents of the PGC-1 signaling network, but also potentiated myogenic differentiation associated increases in mitochondrial respiration, mitochondrial DNA copy number, oxidative phosphorylation (OXPHOS) protein abundance and the activity of key enzymes involved in the Krebs cycle and fatty acid beta-oxidation. In addition, GSK-3 beta KO animals showed augmented reloading-induced increases in skeletal muscle gene expression of constituents of the PGC-1 signaling network as well as sub-units of OXPHOS complexes compared to wild-type animals.Conclusion: Inactivation of GSK-3 beta stimulates activation of PGC-1 signaling and mitochondrial biogenesis during myogenic differentiation and reloading of the skeletal musculature.

AB - Background: Mitochondria] biogenesis is crucial for myogenic differentiation and regeneration of skeletal muscle tissue and is tightly controlled by the peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC-1) signaling network. In the present study, we hypothesized that inactivation of glycogen synthase kinase (GSK)-3 beta, previously suggested to interfere with PGC-1 in non-muscle cells, potentiates PGC-1 signaling and the development of mitochondrial biogenesis during myogenesis, ultimately resulting in an enhanced myotube oxidative capacity.Methods: GSK-3 beta was inactivated genetically or pharmacologically during myogenic differentiation of C2C12 muscle cells. In addition, m. gastrocnemius tissue was collected from wild-type and muscle-specific GSK-3 beta knockout (KO) mice at different time-points during the reloading/regeneration phase following a 14-day hind-limb suspension period. Subsequently, expression levels of constituents of the PGC-1 signaling network as well as key parameters of mitochondrial oxidative metabolism were investigated.Results: In vitro, both knock-down as well as pharmacological inhibition of GSK-3 beta not only increased expression levels of important constituents of the PGC-1 signaling network, but also potentiated myogenic differentiation associated increases in mitochondrial respiration, mitochondrial DNA copy number, oxidative phosphorylation (OXPHOS) protein abundance and the activity of key enzymes involved in the Krebs cycle and fatty acid beta-oxidation. In addition, GSK-3 beta KO animals showed augmented reloading-induced increases in skeletal muscle gene expression of constituents of the PGC-1 signaling network as well as sub-units of OXPHOS complexes compared to wild-type animals.Conclusion: Inactivation of GSK-3 beta stimulates activation of PGC-1 signaling and mitochondrial biogenesis during myogenic differentiation and reloading of the skeletal musculature.

KW - GSK-3 beta

KW - Myogenic differentiation

KW - Myogenesis

KW - PGC-1 and mitochondrial biogenesis

KW - PROLIFERATOR-ACTIVATED RECEPTOR

KW - ADULT SKELETAL-MUSCLE

KW - OBSTRUCTIVE PULMONARY-DISEASE

KW - PDK4 GENE-EXPRESSION

KW - ERR-ALPHA

KW - OXIDATIVE CAPACITY

KW - SATELLITE CELLS

KW - HEART-FAILURE

KW - MYOBLAST DIFFERENTIATION

KW - TRANSCRIPTIONAL CONTROL

U2 - 10.1016/j.bbadis.2018.06.002

DO - 10.1016/j.bbadis.2018.06.002

M3 - Article

C2 - 29883716

SN - 0925-4439

VL - 1864

SP - 2913

EP - 2926

JO - Biochimica et Biophysica Acta-Molecular Basis of Disease

JF - Biochimica et Biophysica Acta-Molecular Basis of Disease

IS - 9

ER -

Inactivation of glycogen synthase kinase 3 beta (GSK-3 beta) enhances mitochondrial biogenesis during myogenesis

Abstract

Keywords

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