Burn-induced increase in atrogin-1 and MuRF-1 in skeletal muscle is glucocorticoid independent but downregulated by IGF-I.

Abstract

The present study determined whether thermal injury increases the expression of the ubiquitin (Ub) E3 ligases referred to as muscle ring finger (MuRF)-1 and muscle atrophy F-box (MAFbx; aka atrogin-1), which are muscle specific and responsible for the increased protein breakdown observed in other catabolic conditions. After 48 h of burn injury (40% total body surface area full-thickness scald burn) gastrocnemius weight was reduced, and this change was associated with an increased mRNA abundance for atrogin-1 and MuRF-1 (3.1- to 8-fold, respectively). Similarly, burn increased polyUb mRNA content in the gastrocnemius twofold. In contrast, there was no burn-induced atrophy of the soleus and no significant change in atrogin-1, MuRF-1, or polyUb mRNA. Burns also did not alter E3 ligase expression in heart. Four hours after administration of the anabolic agent insulin-like growth factor (IGF)-I to burned rats, the mRNA content of atrogin-1 and polyUb in gastrocnemius had returned to control values and the elevation in MuRF-1 was reduced 50%. In contrast, leucine did not alter E3 ligase expression. In a separate study, in vivo administration of the proteasome inhibitor Velcade prevented burn-induced loss of muscle mass determined at 48 h. Finally, administration of the glucocorticoid receptor antagonist RU-486 did not prevent burn-induced atrophy of the gastrocnemius or the associated elevation in atrogin-1, MuRF-1, or polyUb. In summary, the acute muscle wasting accompanying thermal injury is associated with a glucocorticoid-independent increase in the expression of several Ub E3 ligases that can be downregulated by IGF-I.

• Authors: Charles H Lang, Danuta Huber, Robert A Frost
• Journal: American journal of physiology. Regulatory, integrative and comparative physiology (Am J Physiol Regul Integr Comp Physiol) Vol. 292 Issue 1 Pg. R328-36 (Jan 2007) ISSN: 0363-6119 [Print] United States
• PMID: 16946078 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Boronic Acids
• Glucocorticoids
• Hormone Antagonists
• Muscle Proteins
• Protein Synthesis Inhibitors
• Pyrazines
• RNA, Messenger
• Tripartite Motif Proteins
• Ubiquitin
• Polyubiquitin
• Mifepristone
• Insulin-Like Growth Factor I
• Bortezomib
• Fbxo32 protein, rat
• SKP Cullin F-Box Protein Ligases
• Trim63 protein, rat
• Ubiquitin-Protein Ligases
• Leucine

Topics

• Animals
• Blotting, Northern
• Boronic Acids (pharmacology)
• Bortezomib
• Burns (complications, metabolism)
• Down-Regulation (drug effects)
• Glucocorticoids (antagonists & inhibitors, physiology)
• Hormone Antagonists (pharmacology)
• Immunoblotting
• Insulin-Like Growth Factor I (pharmacology)
• Leucine (pharmacology)
• Male
• Mifepristone (pharmacology)
• Muscle Proteins (biosynthesis, genetics, metabolism)
• Muscle, Skeletal (drug effects, metabolism)
• Myocardium (metabolism)
• Organ Size (drug effects)
• Polyubiquitin (metabolism)
• Protein Synthesis Inhibitors (pharmacology)
• Pyrazines (pharmacology)
• RNA, Messenger (biosynthesis)
• Rats
• Rats, Wistar
• SKP Cullin F-Box Protein Ligases (biosynthesis, genetics)
• Tripartite Motif Proteins
• Ubiquitin (metabolism)
• Ubiquitin-Protein Ligases (biosynthesis, genetics)
• Wasting Syndrome (etiology, metabolism)