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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    • "Therefore, these data indicate that atrogin-1 and MuRF1 expression by the Ubiquitin Proteasome System in skeletal muscle atrophy can be considered a reliable marker [14] [15] [16] [17] [18]. "
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    ABSTRACT: Purpose: The effect of BCAA (branched chain amino acid) administration on muscle atrophy during growth phases is not well known. We investigated whether BCAA administration can prevent the muscle atrophy induced by hindlimb suspension in growing male rats. Methods: Male Wistar rats were assigned to 1 of 2 groups (n = 7/group): hindlimb suspension and hindlimb suspension with oral BCAA administration (600 mg·kg(-1)·day(-1), valine 1: leucine 2: isoleucine 1). After 14 days of hindlimb suspension, the weight and mRNA levels of the soleus muscle were measured. Results: BCAA administration prevented a decrease in soleus muscle weight. BCAA administration attenuated atrogin-1 and MuRF1 mRNA expression, which has been reported to play a pivotal role in muscle atrophy. Conclusion: BCAA could serve as an effective supplement for the prevention or treatment of muscle atrophy, especially atrophy caused by weightlessness.
    11/2015; 19(3):183-9. DOI:10.5717/jenb.2015.15062704
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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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    • "Glucocorticoids cause muscle atrophy by upregulating the expression of two muscle-specific ubiquitin ligases, MuRF1 and MAFbx/Atrogin1 (Glass 2010). MuRF1 ubiquitinates troponin I, myosin heavy chain, and myosin binding protein C, and thus induces their proteasomal degradation (Clarke et al. 2007, Polge et al. 2011). In contrast, MAFbx/Atrogin1 suppresses protein synthesis through the ubiquitination and degradation of eIF3f and MyoD, key factors regulating translation and transcription in muscle respectively (Attaix & Baracos 2010). "
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    ABSTRACT: Glucocorticoids play a major role in the development of muscle atrophy in various medical conditions, such as cancer, burn injury, and sepsis, by inhibiting insulin signaling. In this study, we report a new pathway in which glucocorticoids reduce the levels of upstream insulin signaling components by downregulating the transcription of caveolin-1 (Cav1), a scaffolding protein present in the caveolar membrane. Treatment with the glucocorticoid dexamethasone decreased Cav1 protein and mRNA expression, with a concomitant reduction in insulin receptor α (IRα) and insulin receptor substrate-1 (IRS1) levels in C2C12 myotubes. Promoter analysis using deletion mutants and site-directed mutagenesis identified a negative glucocorticoid-response element in the regulatory region of the Cav1 gene, confirming that Cav1 is a glucocorticoid target gene. Cav1 knockdown using siRNA decreased the protein levels of IRα and IRS1, and overexpression of Cav1 prevented the dexamethasone-induced decrease in IRα and IRS1 proteins, demonstrating a causal role of Cav1 in the inhibition of insulin signaling. Moreover, injection of adenovirus expressing Cav1 into the gastrocnemius muscle of mice prevented dexamethasone-induced atrophy. These results indicate that Cav1 is a critical regulator of muscle homeostasis, linking glucocorticoid signaling to the insulin signaling pathway, thereby providing a novel target for the prevention of glucocorticoid-induced muscle atrophy.
    Journal of Endocrinology 02/2015; 225(1). DOI:10.1530/JOE-14-0490 · 3.72 Impact Factor
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