During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation.
Loss of myofibrillar proteins is a hallmark of atrophying muscle. Expression of muscle RING-finger 1 (MuRF1), a ubiquitin ligase, is markedly induced during atrophy, and MuRF1 deletion attenuates muscle wasting. We generated mice expressing a Ring-deletion mutant MuRF1, which binds but cannot ubiquitylate substrates. Mass spectrometry of the bound proteins in denervated muscle identified many myofibrillar components. Upon denervation or fasting, atrophying muscles show a loss of myosin-binding protein C (MyBP-C) and myosin light chains 1 and 2 (MyLC1 and MyLC2) from the myofibril, before any measurable decrease in myosin heavy chain (MyHC). Their selective loss requires MuRF1. MyHC is protected from ubiquitylation in myofibrils by associated proteins, but eventually undergoes MuRF1-dependent degradation. In contrast, MuRF1 ubiquitylates MyBP-C, MyLC1, and MyLC2, even in myofibrils. Because these proteins stabilize the thick filament, their selective ubiquitylation may facilitate thick filament disassembly. However, the thin filament components decreased by a mechanism not requiring MuRF1.
Cohen
Shenhav
S
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Brault
Jeffrey J
JJ
Gygi
Steven P
SP
Glass
David J
DJ
Valenzuela
David M
DM
Gartner
Carlos
C
Latres
Esther
E
Goldberg
Alfred L
AL
D000205:Actomyosin / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003714:Denervation; D005215:Fasting / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology; D009210:Myofibrils / Q000737:chemistry / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism; D011485:Protein Binding; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000099163:Myosin Binding Protein C
D000205:Actomyosin; D002352:Carrier Proteins; D009124:Muscle Proteins; D018994:Myosin Light Chains; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000099163:Myosin Binding Protein C; C499084:Trim63 protein, mouse