Glycogen synthase kinase-3β is required for the induction of skeletal muscle atrophy.

Abstract

Skeletal muscle atrophy commonly occurs in acute and chronic disease. The expression of the muscle-specific E3 ligases atrogin-1 (MAFbx) and muscle RING finger 1 (MuRF1) is induced by atrophy stimuli such as glucocorticoids or absence of IGF-I/insulin and subsequent Akt signaling. We investigated whether glycogen synthase kinase-3β (GSK-3β), a downstream molecule in IGF-I/Akt signaling, is required for basal and atrophy stimulus-induced expression of atrogin-1 and MuRF1, and myofibrillar protein loss in C(2)C(12) skeletal myotubes. Abrogation of basal IGF-I signaling, using LY294002, resulted in a prominent induction of atrogin-1 and MuRF1 mRNA and was accompanied by a loss of myosin heavy chain fast (MyHC-f) and myosin light chains 1 (MyLC-1) and -3 (MyLC-3). The synthetic glucocorticoid dexamethasone (Dex) also induced the expression of both atrogenes and likewise resulted in the loss of myosin protein abundance. Genetic ablation of GSK-3β using small interfering RNA resulted in specific sparing of MyHC-f, MyLC-1, and MyLC-3 protein levels after Dex treatment or impaired IGF-I/Akt signaling. Interestingly, loss of endogenous GSK-3β suppressed both basal and atrophy stimulus-induced atrogin-1 and MuRF1 expression, whereas pharmacological GSK-3β inhibition, using CHIR99021 or LiCl, only reduced atrogin-1 mRNA levels in response to LY294002 or Dex. In conclusion, our data reveal that myotube atrophy and myofibrillar protein loss are GSK-3β dependent, and demonstrate for the first time that basal and atrophy stimulus-induced atrogin-1 mRNA expression requires GSK-3β enzymatic activity, whereas MuRF1 expression depends solely on the physical presence of GSK-3β.

• Authors: Koen J P Verhees, Annemie M W J Schols, Marco C J M Kelders, Céline M H Op den Kamp, Jos L J van der Velden, Ramon C J Langen
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 301 Issue 5 Pg. C995-C1007 (Nov 2011) ISSN: 1522-1563 [Electronic] United States
• PMID: 21832246 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chir 99021
• Chromones
• Enzyme Inhibitors
• Morpholines
• Muscle Proteins
• Myosin Light Chains
• Pyridines
• Pyrimidines
• RNA, Small Interfering
• Tripartite Motif Proteins
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Insulin-Like Growth Factor I
• Dexamethasone
• Fbxo32 protein, mouse
• SKP Cullin F-Box Protein Ligases
• Trim63 protein, mouse
• Ubiquitin-Protein Ligases
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Glycogen Synthase Kinase 3
• Myosin Heavy Chains
• Lithium Chloride

Topics

• Animals
• Cell Line
• Chromones (pharmacology)
• Dexamethasone (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, metabolism)
• Glycogen Synthase Kinase 3 beta
• Insulin-Like Growth Factor I (antagonists & inhibitors)
• Lithium Chloride (pharmacology)
• Mice
• Morpholines (pharmacology)
• Muscle Proteins (biosynthesis)
• Muscle, Skeletal (drug effects, enzymology)
• Muscular Atrophy (drug therapy, enzymology)
• Myoblasts (drug effects, enzymology, physiology)
• Myosin Heavy Chains (biosynthesis)
• Myosin Light Chains (biosynthesis)
• Pyridines (pharmacology)
• Pyrimidines (pharmacology)
• RNA, Small Interfering (metabolism)
• SKP Cullin F-Box Protein Ligases (biosynthesis)
• Signal Transduction (drug effects)
• Tripartite Motif Proteins
• Ubiquitin-Protein Ligases (biosynthesis)