MuRF1 is a muscle fiber-type II associated factor and together with MuRF2 regulates type-II fiber trophicity and maintenance.
MuRF1 is a member of the RBCC (RING, B-box, coiled-coil) superfamily that has been proposed to act as an atrogin during muscle wasting. Here, we show that MuRF1 is preferentially induced in type-II muscle fibers after denervation. Fourteen days after denervation, MuRF1 protein was further elevated but remained preferentially expressed in type-II muscle fibers. Consistent with a fiber-type dependent function of MuRF1, the tibialis anterior muscle (rich in type-II muscle fibers) was considerably more protected in MuRF1-KO mice from muscle wasting when compared to soleus muscle with mixed fiber-types. We also determined fiber-type distributions in MuRF1/MuRF2 double-deficient KO (dKO) mice, because MuRF2 is a close homolog of MuRF1. MuRF1/MuRF2 dKO mice showed a profound loss of type-II fibers in soleus muscle. As a potential mechanism we identified the interaction of MuRF1/MuRF2 with myozenin-1, a calcineurin/NFAT regulator and a factor required for maintenance of type-II muscle fibers. MuRF1/MuRF2 dKO mice had lost myozenin-1 expression in tibialis anterior muscle, implicating MuRF1/MuRF2 as regulators of the calcineurin/NFAT pathway. In summary, our data suggest that expression of MuRF1 is required for remodeling of type-II fibers under pathophysiological stress states, whereas MuRF1 and MuRF2 together are required for maintenance of type-II fibers, possibly via the regulation of myozenin-1.
Moriscot
Anselmo S
AS
Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, Lineu Prestes Av., 1524, 05508-900 Sao Paulo, SP, Brazil.
Baptista
Igor L
IL
Bogomolovas
Julius
J
Witt
Christian
C
Hirner
Stephanie
S
Granzier
Henk
H
Labeit
Siegfried
S
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003714:Denervation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins; D018656:Muscle Fibers, Fast-Twitch / Q000166:cytology / Q000502:physiology*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; C523647:Myoz1 protein, mouse; C523646:Myoz2 protein, mouse; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; C502755:muscle RING finger 2 protein, mouse; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D018995:Myosin Heavy Chains