Hsp27 inhibits IKKbeta-induced NF-kappaB activity and skeletal muscle atrophy.
Heat shock protein 25/27 (Hsp25/27) is a cytoprotective protein that is ubiquitously expressed in most cells, and is up-regulated in response to cellular stress. Previous work, in nonmuscle cells, has shown that Hsp27 inhibits TNF-alpha-induced NF-kappaB activation. During skeletal muscle disuse, Hsp25/27 levels are decreased and NF-kappaB activity increased, and this increase in NF-kappaB activity is required for disuse muscle atrophy. Therefore, the purpose of the current study was to determine whether electrotransfer of Hsp27 into the soleus muscle of rats, prior to skeletal muscle disuse, is sufficient to inhibit skeletal muscle disuse atrophy and NF-kappaB activation. The 35% disuse muscle-fiber atrophy observed in nontransfected fibers was attenuated by 50% in fibers transfected with Hsp27. Hsp27 also inhibited the disuse-induced increase in MuRF1 and atrogin-1 transcription by 82 and 40%, respectively. Furthermore, disuse- and IKKbeta-induced NF-kappaB transactivation were abolished by Hsp27. In contrast, Hsp27 had no effect on Foxo transactivation. In conclusion, Hsp27 is a negative regulator of NF-kappaB in skeletal muscle, in vivo, and is sufficient to inhibit MuRF1 and atrogin-1 and attenuate skeletal muscle disuse atrophy.
Dodd
Stephen L
SL
Department of Applied Physiology and Kinesiology, 25 Stadium Rd., University of Florida, Gainesville, FL 32611, USA.
Hain
Brian
B
Senf
Sarah M
SM
Judge
Andrew R
AR
D000818:Animals; D001284:Atrophy / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000378:metabolism*; D008297:Male; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044843:SKP Cullin F-Box Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics; D014158:Transcription, Genetic; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics; D000071161:Forkhead Box Protein O1
D051858:Forkhead Transcription Factors; D055551:HSP27 Heat-Shock Proteins; D051550:I-kappa B Kinase; D009124:Muscle Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D044843:SKP Cullin F-Box Protein Ligases; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; C486114:Hspb1 protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C486692:Fbxo32 protein, rat; C499086:Trim63 protein, rat