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Biochim Biophys Acta Mol Basis Dis. 2018 Sep;1864(9 Pt B):2913-2926. doi: 10.1016/j.bbadis.2018.06.002. Epub 2018 Jun 6.

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

Author information

1
NUTRIM School of Nutrition and Translational Research in Metabolism, Department of Respiratory Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands.
2
NUTRIM School of Nutrition and Translational Research in Metabolism, Department of Respiratory Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands. Electronic address: h.gosker@maastrichtuniversity.nl.
3
NUTRIM School of Nutrition and Translational Research in Metabolism, Department of Pharmacology and Toxicology, Maastricht University Medical Center+, Maastricht, The Netherlands.

Abstract

BACKGROUND:

Mitochondrial biogenesis is crucial for myogenic differentiation and regeneration of skeletal muscle tissue and is tightly controlled by the peroxisome proliferator-activated receptor-γ co-activator 1 (PGC-1) signaling network. In the present study, we hypothesized that inactivation of glycogen synthase kinase (GSK)-3β, 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-3β 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-3β knock-out (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-3β 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 β-oxidation. In addition, GSK-3β 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-3β stimulates activation of PGC-1 signaling and mitochondrial biogenesis during myogenic differentiation and reloading of the skeletal musculature.

KEYWORDS:

GSK-3β; Myogenesis; Myogenic differentiation; PGC-1 and mitochondrial biogenesis

PMID:
29883716
DOI:
10.1016/j.bbadis.2018.06.002
[Indexed for MEDLINE]
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