Inactivation of glycogen synthase kinase 3β (GSK-3β) enhances skeletal muscle oxidative metabolism
| Autor: | Alexander Remels, Koen Verhees, Harry Gosker, Annemie Schols, Ramon Langen |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
chemistry.chemical_classification
medicine.medical_specialty Myogenesis Skeletal muscle Peroxisome proliferator-activated receptor Metabolism Oxidative phosphorylation Biology medicine.anatomical_structure Endocrinology Mitochondrial biogenesis chemistry GSK-3 Internal medicine medicine biology.protein Glycogen synthase |
| Zdroj: | 6.4 Genes and Environment. |
| DOI: | 10.1183/13993003.congress-2015.pa1226 |
| Popis: | Background: Linked to physical inactivity, loss of muscle oxidative metabolism is a consistent finding in COPD. Evidence in non-muscle cells shows that glycogen synthase kinase-3β (GSK-3β) represses mitochondrial biogenesis and inhibits PPAR-γ co-activator 1 (PGC-1), a main regulator of cellular oxidative metabolism. Aims: We hypothesized that GSK-3β inactivation enhances muscle oxidative metabolism and protects against physical inactivity-induced loss of oxidative gene expression through activation of PGC-1. Methods: GSK-3β was modulated genetically and pharmacologically in C2C12 myotubes in vitro and in muscle in vivo . Wild-type and muscle-specific GSK-3β knock-out (KO) mice were subjected to hind limb suspension. Key constituents and regulators of oxidative metabolism were investigated. Results: GSK-3β KO animals had increased protein levels of oxidative phosphorylation (OXPHOS) complexes and were protected against unloading-induced decrements in oxidative metabolic gene expression. In vitro , knock-down or inhibition of GSK-3β not only increased cellular O 2 consumption, OXPHOS protein and mRNA abundance and activity of oxidative metabolic enzymes but also dramatically enhanced expression of PGC-1α signaling constituents. Conversely, GSK-3β over-expression in myotubes and expression of a GSK-3α/β mutant resistant to inactivation in vivo decreased muscle OXPHOS expression and reduced expression levels of PGC-1 signaling constituents. Conclusion: Inactivation of GSK-3β boosts skeletal muscle mitochondrial metabolism and protects against inactivity-induced impairment of muscle oxidative capacity. Sponsored by the Netherlands9 Lung Foundation (3.2.09.068) and by NWO (016.126.044). |
| Databáze: | OpenAIRE |
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