| First Author | Theeuwes WF | Year | 2017 |
| Journal | Biochim Biophys Acta | Volume | 1863 |
| Issue | 12 | Pages | 3075-3086 |
| PubMed ID | 28943449 | Mgi Jnum | J:255669 |
| Mgi Id | MGI:6105400 | Doi | 10.1016/j.bbadis.2017.09.018 |
| Citation | Theeuwes WF, et al. (2017) Inactivation of glycogen synthase kinase-3beta (GSK-3beta) enhances skeletal muscle oxidative metabolism. Biochim Biophys Acta 1863(12):3075-3086 |
| abstractText | 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-3beta (GSK-3beta) represses mitochondrial biogenesis and inhibits PPAR-gamma co-activator 1 (PGC-1), a master regulator of cellular oxidative metabolism. The role of GSK-3beta in the regulation of skeletal muscle oxidative metabolism is unknown. AIMS: We hypothesized that inactivation of GSK-3beta stimulates muscle oxidative metabolism by activating PGC-1 signaling and explored if GSK-3beta inactivation could protect against physical inactivity-induced alterations in skeletal muscle oxidative metabolism. METHODS: GSK-3beta was modulated genetically and pharmacologically in C2C12 myotubes in vitro and in skeletal muscle in vivo. Wild-type and muscle-specific GSK-3beta 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-3beta 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-3beta increased transcript and protein abundance of key constituents and regulators of mitochondrial energy metabolism. Furthermore, GSK-3beta KO animals were protected against unloading-induced decrements in expression levels of these constituents. CONCLUSION: Inactivation of GSK-3beta up-regulates skeletal muscle mitochondrial metabolism and increases expression levels of PGC-1 signaling constituents. In vivo, GSK-3beta KO protects against inactivity-induced reductions in muscle metabolic gene expression. |
