MuRF1-dependent Regulation of Systemic Carbohydrate Metabolism as Revealed from Transgenic Mouse Studies

Hirner, Stephanie; Krohne, Christian; Schuster, Alexander; Hoffmann, Sigrid; Witt, Stephanie H.; Erber, Ralf; Sticht, Carsten; Gasch, Alexander; Labeit, Siegfried; Labeit, D.

doi:10.1016/j.jmb.2008.03.049

Cited by 77 publications

(86 citation statements)

References 38 publications

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“…Strong evidence linking FoxO1 expression to skeletal muscle atrophy through the upregulation of genes associated with muscle protein degradation, including MAFbx/atrogin-1 and MuRF-1, has been provided through the use of in vitro and in vivo models (15,19,22,25,26,32). As reported previously (22,36), our findings show that the responsiveness of MuRF-1 to FoxO1 activation is relatively blunted compared with the robust increase in MAFbx/atrogin-1 gene expression.…”

Section: Discussionsupporting

confidence: 80%

“…Although it cannot be discerned from our data, the differential response in expression of these proteins induced through FoxO1 activation may be reflective of different roles of MAFbx/atrogin-1 and MuRF-1 in regulating muscle homeostasis. For instance, overexpression of MAFbx/atrogin-1 in C 2 C 12 skeletal myotubes has been shown to be a powerful inducer of muscle atrophy (5), whereas Hirner et al (19) failed to show muscle atrophy in the presence of genetic overexpression of MuRF-1 in the rodent model. Rather, they observed interaction of MuRF-1 with several genes associated with carbohydrate metabolism, including pyruvate dehydrogenase, phosphoinositide-dependent kinase-2, and phosphoinositide-dependent kinase-4.…”

Section: Discussionmentioning

confidence: 99%

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FoxO1 induces apoptosis in skeletal myotubes in a DNA-binding-dependent manner

McLoughlin

Smith

DeLong

et al. 2009

American Journal of Physiology-Cell Physiology

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Recent studies indicate that FoxO transcription factors play an important role in promoting muscle atrophy. To study mechanisms mediating effects of FoxO proteins on muscle wasting, FoxO1-estrogen receptor fusion proteins that are activated by treatment with 4-hydroxytamoxifen (4-OH-T) were stably transfected in C(2)C(12) skeletal myoblasts using the pBABE retroviral system and grown into multinucleated skeletal myotubes. Activation of FoxO1 resulted in significant muscle atrophy, which was accompanied by DNA fragmentation, evidenced by terminal deoxynucleotidyl transferase dUTP-mediated nick end labeling. Cells expressing a DNA-binding-deficient form of FoxO1 also exhibited significant atrophy on FoxO1 activation but no hallmark signs of apoptosis. FoxO1 activation resulted in a significant increase in muscle atrophy F-box (MAFbx)/atrogin-1, muscle-specific RING finger protein 1 (MuRF-1), and Bcl-2-interacting mediator of cell death (Bim) gene expression, with no significant increase in Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNip3) gene expression. Although the ability of FoxO1 to induce MuRF-1 gene expression appeared to be independent of DNA binding, expression of MAFbx/atrogin-1 and Bim was significantly blunted in cells expressing DNA-binding-deficient FoxO1. BNip3 gene expression was significantly elevated in DNA-binding-deficient mutant cells. These findings indicate that FoxO1 promotes skeletal muscle atrophy through induction of proteolytic and apoptotic machinery via DNA-binding-dependent and -independent mechanisms.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

FoxO1 induces apoptosis in skeletal myotubes in a DNA-binding-dependent manner

McLoughlin

Smith

DeLong

et al. 2009

American Journal of Physiology-Cell Physiology

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“…Thus, MuRF1 either ubiquitylates most proteins being degraded 10 d after denervation, or its actions allow other ligases to act. In either case, MuRF1 clearly is a very general ligase affecting many contractile (Table I), soluble, and nuclear proteins (unpublished data), as was also suggested by two-hybrid studies (Witt et al, 2005;Hirner et al, 2008). Moreover, our studies implicate ubiquitylation by MuRF1 in the selective loss of MyBP-C, MyLC1, and MyLC2, as well as the slower degradation of MyHC, and thereby in the disassembly and degradation of myofibrillar proteins, which is the defining feature of the atrophy process.…”

Section: Discussionsupporting

confidence: 60%

During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation

Cohen¹,

Brault²,

Gygi³

et al. 2009

J Exp Med

123

186

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“…For example, activation of the N-end rule ubiquitin pathway was recently implicated in MyoD degradation in response to DEX in C 2 C 12 cells (49). In addition, transgenic overexpression of MuRF1 was not sufficient to induce atrophy but led to altered levels of enzymes involved in carbohydrate metabolism (16). Thus, consideration of these and other studies, and our present results with GR dim mice, may force a reevaluation of the role of MuRF1 (and possibly even FOXO1 and FOXO3a) in the reduction of muscle mass in catabolic states, although the protein certainly may still play a significant role in structural protein degradation in denervationinduced atrophy.…”

Section: Discussionmentioning

confidence: 99%

“…For example, MuRF1 has been shown to play a direct role in myosin heavy chain ubiquitination and degradation during synthetic glucocorticoid treatment (5). However, MuRF1 may have additional important functions in skeletal muscle, such as inhibition of protein synthesis during starvation conditions (22) as well as regulating carbohydrate metabolism (16). Despite considerable interest in MuRF1 as a regulator of skeletal muscle mass and metabolism, there are limited data on the transcriptional regulation of the MuRF1 gene.…”

mentioning

confidence: 99%

The glucocorticoid receptor and FOXO1 synergistically activate the skeletal muscle atrophy-associated MuRF1 gene

Waddell¹,

Baehr²,

Brandt³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

288

268

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The muscle specific ubiquitin E3 ligase MuRF1 has been implicated as a key regulator of muscle atrophy under a variety of conditions, such as during synthetic glucocorticoid treatment. FOXO class transcription factors have been proposed as important regulators of MuRF1 expression, but its regulation by glucocorticoids is not well understood. The MuRF1 promoter contains a near-perfect palindromic glucocorticoid response element (GRE) 200 base pairs upstream of the transcription start site. The GRE is highly conserved in the mouse, rat, and human genes along with a directly adjacent FOXO binding element (FBE). Transient transfection assays in HepG2 cells and C 2C12 myotubes demonstrate that the MuRF1 promoter is responsive to both the dexamethasone (DEX)-activated glucocorticoid receptor (GR) and FOXO1, whereas coexpression of GR and FOXO1 leads to a dramatic synergistic increase in reporter gene activity. Mutation of either the GRE or the FBE significantly impairs activation of the MuRF1 promoter. Consistent with these findings, DEXinduced upregulation of MuRF1 is significantly attenuated in mice expressing a homodimerization-deficient GR despite no effect on the degree of muscle loss in these mice vs. their wild-type counterparts. Finally, chromatin immunoprecipitation analysis reveals that both GR and FOXO1 bind to the endogenous MuRF1 promoter in C 2C12 myotubes, and IGF-I inhibition of DEX-induced MuRF1 expression correlates with the loss of FOXO1 binding. These findings present new insights into the role of the GR and FOXO family of transcription factors in the transcriptional regulation of the MuRF1 gene, a direct target of the GR in skeletal muscle.forkhead transcription factor class O; muscle RING finger 1; glucocorticoid receptor SKELETAL MUSCLE IS A DYNAMIC TISSUE that has the capacity to continuously regulate its size in response to a variety of external cues, including mechanical load, neural activity, hormones/growth factors, stress, and nutritional status. In addition, skeletal muscle serves as the most significant repository for protein in the body, a source that is tapped to provide a pool of amino acids for tissue repair and gluconeogenesis under conditions of starvation and other metabolic stresses. Muscle loss or "atrophy" occurs as the result of a number of disparate conditions, including aging, immobilization, metabolic diseases, cancer, and neurodegenerative diseases, and as a serious side effect of therapeutic corticosteroid hormone treatment (15,27,32). The recently identified E3 ubiquitin ligase, muscle RING finger 1 (MuRF1

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MuRF1-dependent Regulation of Systemic Carbohydrate Metabolism as Revealed from Transgenic Mouse Studies

Cited by 77 publications

References 38 publications

FoxO1 induces apoptosis in skeletal myotubes in a DNA-binding-dependent manner

FoxO1 induces apoptosis in skeletal myotubes in a DNA-binding-dependent manner

During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation

The glucocorticoid receptor and FOXO1 synergistically activate the skeletal muscle atrophy-associated MuRF1 gene

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