Burn-induced increase in atrogin-1 and MuRF-1 in skeletal muscle is glucocorticoid independent but downregulated by IGF-I.
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.
Lang
Charles H
CH
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. clang@psu.edu
Huber
Danuta
D
Frost
Robert A
RA
D000818:Animals; D015152:Blotting, Northern; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002056:Burns / Q000150:complications / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000502:physiology*; D006727:Hormone Antagonists / Q000494:pharmacology; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007930:Leucine / Q000494:pharmacology; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D025821:Polyubiquitin / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D044843:SKP Cullin F-Box Protein Ligases / Q000096:biosynthesis* / Q000235:genetics; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000235:genetics; D019282:Wasting Syndrome / Q000209:etiology / Q000378:metabolism
D001897:Boronic Acids; D005938:Glucocorticoids; D006727:Hormone Antagonists; D009124:Muscle Proteins; D011500:Protein Synthesis Inhibitors; D011719:Pyrazines; D012333:RNA, Messenger; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; D025821:Polyubiquitin; D015735:Mifepristone; D007334:Insulin-Like Growth Factor I; D000069286:Bortezomib; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases; D007930:Leucine