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Biochim Biophys Acta Mol Basis Dis. 2017 Dec;1863(12):3075-3086. doi: 10.1016/j.bbadis.2017.09.018. Epub 2017 Sep 22.

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

Author information

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

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-3β (GSK-3β) represses mitochondrial biogenesis and inhibits PPAR-γ co-activator 1 (PGC-1), a master regulator of cellular oxidative metabolism. The role of GSK-3β in the regulation of skeletal muscle oxidative metabolism is unknown.

AIMS:

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

METHODS:

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

RESULTS:

In vitro, knock-down of GSK-3β 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-3β increased transcript and protein abundance of key constituents and regulators of mitochondrial energy metabolism. Furthermore, GSK-3β KO animals were protected against unloading-induced decrements in expression levels of these constituents.

CONCLUSION:

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

KEYWORDS:

GSK-3β; Hind limb suspension; Mitochondrial biogenesis; Mitochondrial metabolism; PGC-1α; Skeletal muscle

PMID:
28943449
DOI:
10.1016/j.bbadis.2017.09.018
[Indexed for MEDLINE]
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