The E3 Ligase MuRF1 Degrades Myosin Heavy Chain Protein in Dexamethasone-Treated Skeletal Muscle

Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
Cell Metabolism (Impact Factor: 17.57). 12/2007; 6(5):376-85. DOI: 10.1016/j.cmet.2007.09.009
Source: PubMed


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.

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Available from: Monte Willis, Oct 04, 2015
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    • "Increased expression of atrogin-1 and reduced expression of myogenin had previously been linked to a model of skeletal muscle atrophy [32]. In turn, MuRF-1 controls the half-life of important structural muscle proteins [33] [34] [35], including myosin heavy chains [33] [34]. Neu1 is involved in cell proliferation [15]. "
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    ABSTRACT: Neuraminidase-1 (NEU1) is the sialidase responsible for the catabolism of sialoglycoconjugates in lysosomes. Congenital NEU1 deficiency causes sialidosis, a severe lysosomal storage disease associated with a broad spectrum of clinical manifestations, which also include skeletal deformities, skeletal muscle hypotonia and weakness. Neu1(-/-) mice, a model of sialidosis, develop an atypical form of muscle degeneration caused by progressive expansion of the connective tissue that infiltrates the muscle bed, leading to fiber degeneration and atrophy. Here we investigated the role of Neu1 in the myogenic process that ensues during muscle regeneration after cardiotoxin-induced injury of limb muscles. A comparative analysis of cardiotoxin-treated muscles from Neu1(-/-) mice and Neu1(+/+) mice showed increased inflammatory and proliferative responses in the absence of Neu1 during the early stages of muscle regeneration. This was accompanied by significant and sequential upregulation of Pax7, MyoD, and myogenin mRNAs. The levels of both MyoD and myogenin proteins decreased during the late stages of regeneration, which most likely reflected an increased rate of degradation of the myogenic factors in the Neu1(-/-) muscle. We also observed a delay in muscle cell differentiation, which was characterized by prolonged expression of embryonic myosin heavy chain, as well as reduced myofiber cross-sectional area. At the end of the regenerative process, collagen type III deposition was increased compared to wild-type muscles and internal controls, indicating the initiation of fibrosis. Overall, these results point to a role of Neu1 throughout muscle regeneration. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 05/2015; 1852(9). DOI:10.1016/j.bbadis.2015.05.006 · 4.66 Impact Factor
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    • "and transcription factors [33] [34] [35] [36]. ALP-regulated autophagy clears longlived proteins and dysfunctional organelles through autophagosome formation, which is initiated or aided by proteins like LC3, Gabarapl1 [37] and BNIP3 [38], whose presence is increased in atrophying muscle [37] [39] [40]. "
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    ABSTRACT: Muscle wasting impairs physical performance, increases mortality and reduces medical intervention efficacy in chronic diseases and cancer. Developing proficient intervention strategies requires improved understanding of the molecular mechanisms governing muscle mass wasting and recovery. Involvement of muscle protein- and myonuclear turnover during recovery from muscle atrophy has received limited attention. The insulin-like growth factor (IGF)-I signaling pathway has been implicated in muscle mass regulation. As glycogen synthase kinase 3 (GSK-3) is inhibited by IGF-I signaling, we hypothesized that muscle-specific GSK-3β deletion facilitates the recovery of disuse-atrophied skeletal muscle. Wild-type mice and mice lacking muscle GSK-3β (MGSK-3β KO) were subjected to a hindlimb suspension model of reversible disuse-induced muscle atrophy and followed during recovery. Indices of muscle mass, protein synthesis and proteolysis, and post-natal myogenesis which contribute to myonuclear accretion, were monitored during the reloading of atrophied muscle. Early muscle mass recovery occurred more rapidly in MGSK-3β KO muscle. Reloading-associated changes in muscle protein turnover were not affected by GSK-3β ablation. However, coherent effects were observed in the extent and kinetics of satellite cell activation, proliferation and myogenic differentiation observed during reloading, suggestive of increased myonuclear accretion in regenerating skeletal muscle lacking GSK-3β. This study demonstrates that muscle mass recovery and post-natal myogenesis from disuse-atrophy are accelerated in the absence of GSK-3β. Copyright © 2014. Published by Elsevier B.V.
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 12/2014; 1852(3). DOI:10.1016/j.bbadis.2014.12.006 · 4.88 Impact Factor
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    • "The knockout of each MuRF gene has been achieved in mice, both individually [8] [9] [10] or in combination for MuRF1 and 2 [9], demonstrating the importance of MuRF1 as a regulator of atrophy under catabolic contexts [8] and the individual or combined importance of MuRFs in the normal development [9] and protection of heart muscle [10]. In terms of their roles as E3-ubiquitin ligases, characterized mammalian MuRF targets include major sarcomeric proteins such as myosin heavy chain, myosin light chain and troponin-I , [11] [12] [13], while additional binding partners are known [2] [10] [14] that may or may not be targeted for degradation [2]. Progress made in understanding the functions and regulation of mammalian MuRFs is not mirrored at the evolutionary level. "
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    ABSTRACT: Muscle-specific RING finger (MuRF) proteins are E3-ubiquitin ligases and key regulators of muscle growth and turnover. Here, using a range of phylogenomic approaches, we generated a comprehensive list of members of the vertebrate MuRF family. Adding to the previously-reported MuRF1, MuRF2 and MuRF3, we identified a novel family member, MuRF4, which seems to have been independently lost during placental mammal and bird evolution, but is otherwise conserved. MuRF4 transcripts are expressed in heart and skeletal muscles of zebrafish, but are barely detectable in the striated muscles of adult anole lizards. We also demonstrate that MuRF1 underwent retrotransposition in the teleost fish ancestor, before the retrogene fully replaced the original gene and muscle-specific function.
    FEBS Letters 11/2014; 588(23). DOI:10.1016/j.febslet.2014.10.008 · 3.17 Impact Factor
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