The E3 Ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle.
Skeletal muscle atrophy occurs as a side effect of treatment with synthetic glucocorticoids such as dexamethasone (DEX) and is a hallmark of cachectic syndromes associated with increased cortisol levels. The E3 ubiquitin ligase MuRF1 (muscle RING finger protein 1) is transcriptionally upregulated by DEX treatment. Differentiated myotubes treated with DEX undergo depletion of myosin heavy chain protein (MYH), which physically associates with MuRF1. This loss of MYH can be blocked by inhibition of MuRF1 expression. When wild-type and MuRF1(-/-) mice are treated with DEX, the MuRF1(-/-) animals exhibit a relative sparing of MYH. In vitro, MuRF1 is shown to function as an E3 ubiquitin ligase for MYH. These data identify the mechanism by which MYH is depleted under atrophy conditions and demonstrate that inhibition of a single E3 ligase, MuRF1, is sufficient to maintain this important sarcomeric protein.
Clarke
Brian A
BA
Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
Drujan
Doreen
D
Willis
Monte S
MS
Murphy
Leon O
LO
Corpina
Richard A
RA
Burova
Elena
E
Rakhilin
Sergey V
SV
Stitt
Trevor N
TN
Patterson
Cam
C
Latres
Esther
E
Glass
David J
DJ
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D034622:RNA Interference; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D005938:Glucocorticoids; D007976:Leupeptins; D009124:Muscle Proteins; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D020033:Protein Isoforms; D000070584:Tripartite Motif Proteins; D003907:Dexamethasone; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D018995:Myosin Heavy Chains; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C078846:epoxomicin