Atrogin1/MAFbx
2011; Lippincott Williams & Wilkins; Volume: 109; Issue: 2 Linguagem: Inglês
10.1161/circresaha.111.248872
ISSN1524-4571
AutoresDonghoon Lee, Alfred L. Goldberg,
Tópico(s)Cardiovascular Effects of Exercise
ResumoHomeCirculation ResearchVol. 109, No. 2Atrogin1/MAFbx Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBAtrogin1/MAFbxWhat Atrophy, Hypertrophy, and Cardiac Failure Have in Common Donghoon Lee and Alfred Goldberg Donghoon LeeDonghoon Lee From the Department of Cell Biology, Harvard Medical School, Boston, MA. and Alfred GoldbergAlfred Goldberg From the Department of Cell Biology, Harvard Medical School, Boston, MA. Originally published8 Jul 2011https://doi.org/10.1161/CIRCRESAHA.111.248872Circulation Research. 2011;109:123–126See related article, pages 161–171Proteins in cardiac and skeletal muscle cells, as in other cells, are continually being synthesized and degraded back to their constituent amino acids. Protein turnover in cardiac myocytes utilizes the same proteolytic systems as other eukaryotic cells: the ubiquitin-proteasome pathway, which catalyzes the rapid degradation of misfolded and regulatory proteins, and the lysosomal-autophagic system, which degrades organelles and aggregated proteins. These systems are of major importance in determining cardiac size and functional capacity. The overall rates of proteolysis in a cell and the degradation of individual components are precisely regulated. For example, cardiac hypertrophy occurs when overall rates of protein synthesis exceed overall rates of protein degradation; conversely cells decrease in mass when degradation rates exceed synthesis, as occurs in skeletal muscle with disuse, fasting, and many systemic diseases, including cardiac failure. In addition, the levels of individual proteins, whether they are enzymes, transcription factors, or components of the sarcomere, are determined in large part by their rates of ubiquitin-mediated degradation. In this issue of Circulation Research, Usui et al1 demonstrate how a single ubiquitination enzyme can have major effects on cardiac growth and function.In this pathway, proteins are targeted for degradation by the 26S proteasome by covalent attachment of a chain of ubiquitin molecules. This multistep pathway first involves the activation of the small protein ubiquitin by an enzyme, E1, which then transfers the highly reactive ubiquitin to one of the cell's many ubiquitin-conjugating enzymes, E2s. A ubiquitin protein ligase, E3, then binds the protein substrate and the ubiquitin-E2 and catalyzes the formation of a chain of ubiquitins on the protein. Different E2-E3 pairs function in the degradation of different proteins, and the specificity of the E3s for specific groups of proteins provides exquisite selectivity to this degradation process. The content of different E2s and E3s varies between tissues and with different physiological conditions (as is nicely illustrated by the findings of Usui et al), but which E2s and E3s function normally in cardiac muscle is unknown. The human genome contains over 650 ubiquitin ligases, which makes possible precise regulation of different cell processes, and in recent years, dramatic progress has been made in elucidating the roles of different E3s in regulating metabolism, transcription, cell cycle, oncogenesis, and so forth. Although the pharmacological modulation of specific ubiquitin ligases is an attractive approach for treating many diseases, this possibility has thus far not been exploited, although an inhibitor of the proteasome (Bortezomib) is now widely used in the treatment for certain hematologic cancers. In this regard, it is intriguing that proteasome inhibitors also attenuate or reverse cardiac hypertrophy in multiple rodent models.2Atrogin1, Also Known as MAFbx, Is Critical for Skeletal Muscle Atrophy and Cardiac HypertrophyThe article by Usui et al has uncovered an important, unexpected role of the ubiquitin ligase Atrogin1/MAFbx in cardiac hypertrophy. Their finding is particularly surprising because this E3 has been shown to be crucial in skeletal muscle atrophy. In fact, because of its dramatic induction in nearly all forms of muscle atrophy, its expression is widely used as a marker of muscle wasting (especially when accompanied by induction of another atrophy-related ubiquitin ligase, MuRF1). In studies to identify the key mechanisms driving muscle atrophy, about 100 genes were identified that were named atrophy-related genes or atrogenes,3 whose expression was induced or suppressed similarly in rodent muscles undergoing various types of atrophy, including fasting, untreated diabetes, renal failure, acidosis, cancer cachexia, and denervation or disuse.3,4 They were therefore named "atrogenes," for atrophy-related genes. Among this set of genes, Atrogin1/MAFbx was one of the most dramatically induced. It is a muscle-specific E3, present also in cardiac and smooth muscle, although in fasting and catabolic disease, it is induced specifically in skeletal muscles, where proteolysis increases to provide the stressed organism with a supply of amino acids for gluconeogenesis and adaptive responses. A similar induction has been observed in muscles of patients with trauma, sepsis, and renal failure, in which there is marked muscle wasting. In experimental models, induction of Atrogin1 mRNA accompanies the rapid atrophy; that is, within 1 to 3 days after cutting the motor neuron, its level rises maximally and then falls after 14 days back to control level. Thus, high levels of this protein coincide with and help trigger the rapid weight loss.5This gene contains an F-box, a hallmark of a large family of multicomponent ubiquitin ligases. The F-box protein is the substrate-binding subunit that functions in a larger complex together with 3 other subunits (Skp1, Rbx1, and Cullin1) that also function with other F-box proteins in the ubiquitination of other proteins. This ubiquitin ligase was discovered simultaneously by Goldberg's laboratory, who named it Atrogin1 because of its dramatic induction in diverse types of atrophy,3 and by Glass and Yancopoulos's group,6 who named it MAFbx, because it was a muscle F-box protein. Both names, though widely used, now seem inappropriate because a number of other muscle F-box proteins are now known and because it is not specific to atrophy, as shown by Usui et al. They report that Atrogin1/MAFbx is also induced during compensatory hypertrophy of the heart, where it is important for the large increase in cardiac mass after aortic constriction and especially for the growth of cardiac myocytes induced with phenylephrine. In fact, had the present studies appeared 11 years ago, Atrogin1 might have been named Hypertrogin1. Moreover, this E3 appears to contribute particularly to the development or pathological hypertrophy and cardiac failure because MAFbx-knockout animals showed a mild reduction in hypertrophy and a large decrease in various pathological sequelae such as pulmonary congestion and fibrosis and cardiomyocyte apoptosis. This surprising induction in hypertrophy is consistent with the prior finding that its level decreases during cardiac atrophy induced by unloading.Such a dual role in hypertrophy and atrophy is indeed surprising because these processes have opposite consequences and appear to involve quite different signaling mechanisms. Muscle hypertrophy proceeds through increased activity of the PI3K-AKT-FoxO pathway,7 which enhances protein synthesis and suppresses proteolysis, whereas in atrophy, PI3K-AKT signaling is reduced below normal levels, which causes synthesis to fall and proteolysis to rise (Figure in Sandri et al).8Download figureDownload PowerPointFigure. In atrophying skeletal muscles, diverse catabolic stimuli activate FoxO3 and NF-κB transcription factors and induce expression of Atrogin1/MAFbx and MuRF1, which in turn decrease overall protein synthesis and increase protein degradation. Although similar regulation of Atrogin1/MAFbx by FoxO3 is conserved in cardiac muscles, in response to pressure overload or catecholamines, Atrogin1/MAFbx expression in heart increases and degrades IκBα, the inhibitor of NF-κB. It is unclear how the resulting activation of NF-κB triggers the changes in protein turnover that lead to physiological or pathological hypertrophy.To clarify MAFbx function in skeletal muscle, Bodine et al6 generated mice lacking MAFbx and found a decreased loss of weight and fiber diameter on denervation or glucocorticoid treatment. Reduced atrophy was also seen on deletion of the coinduced ubiquitin ligase MuRF1. During atrophy, these two enzymes appear to promote the breakdown of different cell proteins; for example, MuRF1 (unlike Atrogin1) specifically ubiquitinates components of the thick filament.9 Therefore, it will be interesting to learn if expression of MuRF1 also rises during cardiac hypertrophy.In addition, Atrogin1 has been shown to be important in other conditions, including the muscle pain and weakness that can result from treatment with all known statins. A recent elegant study has demonstrated that Atrogin1 is essential for statin-induced myopathy,10 where knockdown of Atrogin1 in zebra fish prevented the muscle damage induced with statins, although its exact role in causing these symptoms is unclear. In addition, smooth muscle cells can undergo compensatory hypertrophy and atrophy. Interestingly, during involution of the uterus, Atrogin1/MAFbx and MuRF1 were induced in smooth muscle cells.11Despite these crucial effects, only a few proteins have thus far been identified as substrates for Atrogin1/MAFbx, and they all appear to be involved in growth-related processes. When overexpressed in myoblasts, this enzyme inhibits cell differentiation12 and promotes degradation of the key muscle transcription factor MyoD and the key activator of protein synthesis, eIF3-f. When Atrogin1 expression was increased, eIF3-f was polyubiquitinated and degraded by proteasomes.13 eIF3-f stimulates the initiation of polypeptide synthesis at the ribosome and is important for the growth of mature muscles. Thus, when eIF3-f was overexpressed in cultured muscle cells, it induced growth, whereas knockdown of eIF3-f reduced myotube size. Thus, although overexpression of MAFbx in mice alone does not cause muscle atrophy, the accelerated degradation of eIF3-f should certainly reduce growth capacity. Whether a similar effect on eIF3-f occurs on Atrogin1 induction during cardiac hypertrophy is an interesting and important issue that was not addressed by Usui et al. In the heart, Atrogin1 also ubiquitinates and reduces the levels of calcineurin A, which is an important factor triggering cardiac hypertrophy in response to pressure overload.14 In cardiac myocytes, overproduction of Atrogin1 also inhibits phenylephrine-induced hypertrophy by decreasing calcineurin A levels.14 The finding that Atrogin1 degrades proteins primarily involved in growth is clearly difficult to reconcile with this protein's newly discovered role in promoting hypertrophy, although it could be important in the induction of cardiac failure.Regulation of Atrogin1/MAFbx ExpressionIn skeletal muscle, the expression of Atrogin1 and MuRF1 are tightly regulated and rise in response to diverse stimuli that promote muscle wasting, including low insulin states, glucocorticoids, acidosis, inactivity, and myostatin. These catabolic stimuli all activate the FoxO family of transcription factors, which mediate transcription of many atrogenes, including Atrogin1, MuRF1, and many genes for autophagy. Consequently, activated FoxO3 by itself induces profound atrophy of skeletal and cardiac muscles.8,15 Conversely, this atrophy program is suppressed by growth factors (eg, insulin-like growth factor-1) that stimulate the PI3K-AKT pathway and thus promote protein synthesis, and by inactivating FoxOs reduce proteolysis.16,17 These two actions together synergize to cause rapid hypertrophy. In addition, the exercise-induced transcription cofactor PGC-1α, which promotes production of mitochondria, also inhibits the activation of FoxO3, and this action helps explain the capacity of exercise to prevent muscle atrophy.18 Despite its importance in regulating Atrogin1 and MuRF1 in catabolic conditions (including cardiac myocytes deprived of growth factors), FoxO3 was not found by Usui et al to be activated during cardiac hypertrophy when Atrogin1 was induced. Thus, it is highly likely that an as-yet unidentified transcription factor responds to pressure overload and catecholamines to trigger transcription of MAFbx. Therefore, the mechanisms signaling Atrogin1 (MAFbx) induction in atrophy and hypertrophy appear to be fundamentally different, although the differences observed thus far might still be explained by differences between heart and skeletal muscles. So, analogous studies of compensatory hypertrophy in skeletal muscle appear important to clarify whether they also express Atrogin1 in response to increased load by a FoxO-independent mechanism.Initially, hearts of mice lacking Atrogin1/MAFbx were reported to exhibit no clear abnormality6; however, their ability to respond to physiological challenges had not been tested until Usui et al made the important finding that Atrogin1/MAFbx is required for maximal hypertrophy, and especially for its pathological consequences (ie, increase in lung congestion, apoptosis of myocardial cells, and decreased left ventricular production of fetal myosin). Among the important, unexpected findings in this report was that deletion of Atrogin1/MAFbx decreased the degradation of IκBα, the inhibitor of nuclear factor (NF)-κB, which is the transcription factor triggering many pathological responses. Conversely, overexpression of Atrogin1/MAFbx promoted the degradation of IκBα and activation of NF-κB. In other cells, these responses are the hallmarks of inflammation and production of inflammatory mediators. In hypertrophied heart, NF-κB had been previously found to rise, and the discovery that Atrogin1/MAFbx ubiquitinates IκBα and thereby is a positive regulator of cardiac NF-κB is an important discovery whose physiological and pathological consequences remain to be defined. In skeletal muscle, NF-κB is necessary for atrophy and is activated together with FoxOs when Atrogin1/MAFbx is induced.19 Perhaps Atrogin1/MAFbx helps trigger its activation in the atrophying muscles.Outstanding QuestionsPuzzling observations and apparent paradoxes in research can be valuable in stimulating additional experimental studies and further progress. Beyond its novel findings, the article by Usui et al raises several perplexing points that certainly merit future in-depth study. Because knockout of Atrogin1/MAFbx diminished hypertrophy, overexpression of this gene would be expected to promote cardiac growth. However, muscle size was decreased by overexpressing MAFbx. Thus, a major puzzle is that both its deletion and overexpression attenuate cardiac hypertrophy. One possible explanation could be that Atrogin1/MAFbx plays a specific role in an initial step promoting hypertrophy (eg, degradation of IκBα), but, subsequently, when Atrogin1/MAFbx levels markedly increase, it may then attenuate muscle growth, as these authors found on its overexpression, and as Atrogin1/MAFbx does in atrophying muscles. Perhaps there are distinct substrates for this E3 in the early and later phases, where pathological consequences and failure become evident that may also result from the buildup of NF-κB.Based on the apparent importance of NF-κB in hypertrophying hearts and in multiple other diseases, it will be illuminating to define its precise effects on cardiac size and function—specifically to learn whether selective downregulation of NF-κB diminishes hypertrophy or overexpression of NF-κB can increase heart size and failure. Such studies could have therapeutic applications because inhibitors of NF-κB are available for clinical study. In skeletal muscle, this transcription factor synergizes with FoxOs in promoting overall proteolysis and atrophy, which should not be of benefit in a compromised heart. Probably, the best studied function of NF-κB in disease is in enhancing the production of inflammatory mediators, including interleukin-1, tumor necrosis factor-α, and interleukin-6, which was found to increase in these hypertrophied hearts by a MAFbx-dependent mechanism. These potent mediators appear to be likely contributors to the development of pathological hypertrophy and cardiac failure. However, another important action of NF-κB in most cells, and especially in many cancers, is in reducing apoptosis. Such an effect in cardiac hypertrophy appears to be likely because it would account for the finding of Usui et al of less apoptosis and less production of the NF-κB–dependent antiapoptotic mediator Bcl-3 in hearts of mice lacking MAFbx. Such effects would be expected to protect myocytes and be beneficial. Thus, NF-κB activation can have both toxic and helpful consequences in the overloaded heart. Finally, these observations emphasize the importance of identifying the major transcription factor triggering Atrogin1/MAFbx expression because it clearly plays a crucial role in cardiac disease and because it is neither FoxO3 nor NF-κB. Moreover, this unknown factor and its activation mechanisms would be very attractive new therapeutic targets.Non-standard Abbreviations and Acronyms eIF3-feukaryotic initiation factor 3-fNFnuclear factorPGC-1αperoxisome proliferator-activated receptor gamma coactivator 1-alphaPI3Kphosphatidylinositol 3-kinaseDisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Alfred Goldberg, PhD, Department of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115. E-mail alfred_goldberg@hms.harvard.eduReferences1. Usui S, Maejima Y, Pain J, Hong C, Cho J, Park JY, Zablocki D, Tian B, Glass DJ, Sadoshima J. Endogenous muscle atrophy f-box mediates pressure overload-induced cardiac hypertrophy through regulation of nuclear factor-κB. Circ Res. 2011; 109:161–171.LinkGoogle Scholar2. Stansfield WE, Tang RH, Moss NC, Baldwin AS, Willis MS, Selzman CH. Proteasome inhibition promotes regression of left ventricular hypertrophy. Am J Physiol Heart Circ Physiol. 2008; 294:H645–H650.CrossrefMedlineGoogle Scholar3. Gomes MD, Lecker SH, Jagoe RT, Navon A, Goldberg AL. Atrogin-1, a muscle-specific f-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci U S A. 2001; 98:14440–14445.CrossrefMedlineGoogle Scholar4. Lecker SH, Jagoe RT, Gilbert A, Gomes M, Baracos V, Bailey J, Price SR, Mitch WE, Goldberg AL. Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J. 2004; 18:39–51.CrossrefMedlineGoogle Scholar5. Sacheck JM, Hyatt JP, Raffaello A, Jagoe RT, Roy RR, Edgerton VR, Lecker SH, Goldberg AL. Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases. FASEB J. 2007; 21:140–155.CrossrefMedlineGoogle Scholar6. Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan ZQ, Valenzuela DM, DeChiara TM, Stitt TN, Yancopoulos GD, Glass DJ. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science. 2001; 294:1704–1708.CrossrefMedlineGoogle Scholar7. Glass DJ. Pi3 kinase regulation of skeletal muscle hypertrophy and atrophy. Curr Top Microbiol Immunol. 2010; 346:267–278.MedlineGoogle Scholar8. Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH, Goldberg AL. FoxO transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. 2004; 117:399–412.CrossrefMedlineGoogle Scholar9. Cohen S, Brault JJ, Gygi SP, Glass DJ, Valenzuela DM, Gartner C, Latres E, Goldberg AL. During muscle atrophy, thick, but not thin, filament components are degraded by murf1-dependent ubiquitylation. J Cell Biol. 2009; 185:1083–1095.CrossrefMedlineGoogle Scholar10. Hanai J, Cao P, Tanksale P, Imamura S, Koshimizu E, Zhao J, Kishi S, Yamashita M, Phillips PS, Sukhatme VP, Lecker SH. The muscle-specific ubiquitin ligase atrogin-1/mafbx mediates statin-induced muscle toxicity. J Clin Invest. 2007; 117:3940–3951.MedlineGoogle Scholar11. Bdolah Y, Segal A, Tanksale P, Karumanchi SA, Lecker SH. Atrophy-related ubiquitin ligases atrogin-1 and murf-1 are associated with uterine smooth muscle involution in the postpartum period. Am J Physiol Regul Integr Comp Physiol. 2007; 292:R971–R976.CrossrefMedlineGoogle Scholar12. Tintignac LA, Lagirand J, Batonnet S, Sirri V, Leibovitch MP, Leibovitch SA. Degradation of myod mediated by the scf (MAFbx) ubiquitin ligase. J Biol Chem. 2005; 280:2847–2856.CrossrefMedlineGoogle Scholar13. Lagirand-Cantaloube J, Offner N, Csibi A, Leibovitch MP, Batonnet-Pichon S, Tintignac LA, Segura CT, Leibovitch SA. The initiation factor eif3-f is a major target for atrogin1/mafbx function in skeletal muscle atrophy. EMBO J. 2008; 27:1266–1276.CrossrefMedlineGoogle Scholar14. Li HH, Kedar V, Zhang C, McDonough H, Arya R, Wang DZ, Patterson C. Atrogin-1/muscle atrophy f-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an scf ubiquitin ligase complex. J Clin Invest. 2004; 114:1058–1071.CrossrefMedlineGoogle Scholar15. Skurk C, Izumiya Y, Maatz H, Razeghi P, Shiojima I, Sandri M, Sato K, Zeng L, Schiekofer S, Pimentel D, Lecker S, Taegtmeyer H, Goldberg AL, Walsh K. The FoxO3a transcription factor regulates cardiac myocyte size downstream of akt signaling. J Biol Chem. 2005; 280:20814–20823.CrossrefMedlineGoogle Scholar16. Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R, Zlotchenko E, Scrimgeour A, Lawrence JC, Glass DJ, Yancopoulos GD. Akt/mtor pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol. 2001; 3:1014–1019.CrossrefMedlineGoogle Scholar17. Shiojima I, Sato K, Izumiya Y, Schiekofer S, Ito M, Liao R, Colucci WS, Walsh K. Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest. 2005; 115:2108–2118.CrossrefMedlineGoogle Scholar18. Sandri M, Lin J, Handschin C, Yang W, Arany ZP, Lecker SH, Goldberg AL, Spiegelman BM. Pgc-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci U S A. 2006; 103:16260–16265.CrossrefMedlineGoogle Scholar19. Cai D, Frantz JD, Tawa NE, Melendez PA, Oh BC, Lidov HG, Hasselgren PO, Frontera WR, Lee J, Glass DJ, Shoelson SE. Ikkbeta/nf-kappab activation causes severe muscle wasting in mice. Cell. 2004; 119:285–298.CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsCited By Shingu Y, Hieda T, Sugimoto S, Asai H, Yamakawa T and Wakasa S (2022) Changes in AMPKα and Ubiquitin Ligases in Myocyte Reverse Remodeling after Surgical Ventricular Reconstruction in rats with ischemic cardiomyopathy, Molecular Biology Reports, 10.1007/s11033-022-07347-8, 49:6, (4885-4892), Online publication date: 1-Jun-2022. Pierucci F, Frati A, Battistini C, Penna F, Costelli P and Meacci E (2021) Control of Skeletal Muscle Atrophy Associated to Cancer or Corticosteroids by Ceramide Kinase, Cancers, 10.3390/cancers13133285, 13:13, (3285) Qi R, Sun J, Qiu X, Zhang Y, Wang J, Wang Q, Huang J, Ge L and Liu Z (2021) The intestinal microbiota contributes to the growth and physiological state of muscle tissue in piglets, Scientific Reports, 10.1038/s41598-021-90881-5, 11:1 Wu J, Zhou Y, Liang C, Zhang X, Lai J, Ye S, Ouyang H, Lin J and Zhou J (2016) Cyclovirobuxinum D alleviates cardiac hypertrophy in hyperthyroid rats by preventing apoptosis of cardiac cells and inhibiting the p38 mitogen-activated protein kinase signaling pathway, Chinese Journal of Integrative Medicine, 10.1007/s11655-015-2299-7, 23:10, (770-778), Online publication date: 1-Oct-2017. Egawa T (2017) Participation of AMPK in the Control of Skeletal Muscle Mass The Plasticity of Skeletal Muscle, 10.1007/978-981-10-3292-9_12, (251-275), . Al-Hassnan Z, Shinwari Z, Wakil S, Tulbah S, Mohammed S, Rahbeeni Z, Alghamdi M, Rababh M, Colak D, Kaya N, Al-Fayyadh M and Alburaiki J (2016) A substitution mutation in cardiac ubiquitin ligase, FBXO32, is associated with an autosomal recessive form of dilated cardiomyopathy, BMC Medical Genetics, 10.1186/s12881-016-0267-5, 17:1, Online publication date: 1-Dec-2016. Sandri M and Robbins J (2014) Proteotoxicity: An underappreciated pathology in cardiac disease, Journal of Molecular and Cellular Cardiology, 10.1016/j.yjmcc.2013.12.015, 71, (3-10), Online publication date: 1-Jun-2014. Pagan J, Seto T, Pagano M and Cittadini A (2013) Role of the Ubiquitin Proteasome System in the Heart, Circulation Research, 112:7, (1046-1058), Online publication date: 29-Mar-2013. Sultan S and Hynes N (2013) The Ugly Side of Statins. Systemic Appraisal of the Contemporary Un-Known Unknowns, Open Journal of Endocrine and Metabolic Diseases, 10.4236/ojemd.2013.33025, 03:03, (179-185), . Bonaldo P and Sandri M (2013) Cellular and molecular mechanisms of muscle atrophy, Disease Models & Mechanisms, 10.1242/dmm.010389, 6:1, (25-39), Online publication date: 1-Jan-2013. Kho A, Perera S, Alexandrovich A and Gautel M (2012) The sarcomeric cytoskeleton as a target for pharmacological intervention, Current Opinion in Pharmacology, 10.1016/j.coph.2012.03.007, 12:3, (347-354), Online publication date: 1-Jun-2012. July 8, 2011Vol 109, Issue 2 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.111.248872PMID: 21737813 Originally publishedJuly 8, 2011 KeywordsNF-κB, ubiquitinprotein degradationatrophyhypertrophyAtrogin1/MAFbxPDF download Advertisement SubjectsGene Expression and RegulationHypertrophy
Referência(s)