Transcription factors in muscle atrophy caused by blocked neuromuscular transmission and muscle unloading in rats.
The muscle wasting associated with long-term intensive care unit (ICU) treatment has a negative effect on muscle function resulting in prolonged periods of rehabilitation and a decreased quality of life. To identify mechanisms behind this form of muscle wasting, we have used a rat model designed to mimic the conditions in an ICU. Rats were pharmacologically paralyzed with a postsynaptic blocker of neuromuscular transmission, and mechanically ventilated for one to two weeks, thereby unloading the limb muscles. Transcription factors were analyzed for cellular localization and nuclear concentration in the fast-twitch muscle extensor digitorum longus (EDL) and in the slow-twitch soleus. Significant muscle wasting and upregulation of mRNA for the ubiquitin ligases MAFbx and MuRF1 followed the treatment. The IkappaB family-member Bcl-3 displayed a concomitant decrease in concentration, suggesting altered kappaB controlled gene expression, although NFkappaB p65 was not significantly affected. The nuclear levels of the glucocorticoid receptor (GR) and the thyroid receptor alpha1 (TRalpha1) were altered and also suggested as potential mediators of the MAFbx- and MuRF1-induction in the absence of induced Foxo1. We believe that this model, and the strategy of quantifying nuclear proteins, will provide a valuable tool for further, more detailed, analyses of the muscle wasting occurring in patients kept on a mechanical ventilator.
Nordquist
Jenny
J
Department of Neuroscience, Clinical Neurophysiology, Uppsala University, Sweden. Jenny.Nordquist@vr.se
Höglund
Anna-Stina
AS
Norman
Holly
H
Tang
Xiaorui
X
Dworkin
Barry
B
Larsson
Lars
L
D000818:Animals; D003039:Cobra Neurotoxin Proteins / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D019417:Hindlimb Suspension; D007150:Immunohistochemistry; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism / Q000473:pathology; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology; D009133:Muscular Atrophy / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism; D014157:Transcription Factors / Q000032:analysis*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D003039:Cobra Neurotoxin Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D037021:Thyroid Hormone Receptors alpha; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; C025154:alpha-cobratoxin; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases; D020928:Mitogen-Activated Protein Kinases