Hsp70 overexpression inhibits NF-kappaB and Foxo3a transcriptional activities and prevents skeletal muscle atrophy.
Heat shock protein 70 (Hsp70) is a highly conserved and ubiquitous protein that is reported to provide cytoprotection in various cell types and tissues. However, the importance of Hsp70 expression during skeletal muscle atrophy, when Hsp70 levels are significantly decreased, is not known. The current study aimed to determine whether plasmid-mediated overexpression of Hsp70, in the soleus muscle of rats, was sufficient to regulate specific atrophy signaling pathways and attenuate skeletal muscle disuse atrophy. We found that Hsp70 overexpression prevented disuse muscle fiber atrophy and inhibited the increased promoter activities of atrogin-1 and MuRF1. Importantly, the transcriptional activities of Foxo3a and NF-kappaB, which are implicated in the regulation of atrogin-1 and MuRF1, were abolished by Hsp70. These data suggest that Hsp70 may regulate key atrophy genes through inhibiting Foxo3a and NF-kappaB activities during disuse. Indeed, we show that specific inhibition of Foxo3a prevented the increases in both atrogin-1 and MuRF1 promoter activities during disuse. However, inhibition of NF-kappaB did not affect the activation of either promoter, suggesting its requirement for disuse atrophy is through its regulation of other atrophy genes. We conclude that overexpression of Hsp70 is sufficient to inhibit key atrophy signaling pathways and prevent skeletal muscle atrophy.
Senf
Sarah M
SM
Department of Applied Physiology and Kinesiology, 25 Stadium Rd., University of Florida, Gainesville, FL 32611, USA.
Dodd
Stephen L
SL
McClung
Joseph M
JM
Judge
Andrew R
AR
D000818:Animals; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D044843:SKP Cullin F-Box Protein Ligases / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics
C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D018840:HSP70 Heat-Shock Proteins; D009124:Muscle Proteins; D016328:NF-kappa B; D000070584:Tripartite Motif Proteins; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases