Ubiquitin-Proteasome-mediated Degradation, Intracellular Localization, and Protein Synthesis of MyoD and Id1 during Muscle Differentiation

Mammalian skeletal myogenesis results in the differentiation of myoblasts to mature syncytial myotubes, a process regulated by an intricate genetic network of at least three protein families: muscle regulatory factors, E proteins, and Id proteins. MyoD, a key muscle regulatory factor, and its negative regulator Id1 have both been shown to be degraded by the ubiquitin-proteasome system. Using C2C12 cells and confocal fluorescence microscopy, we showed that MyoD and Id1 co-localize within the nucleus in proliferating myoblasts. In mature myotubes, in contrast, they reside in distinctive subcellular compartments, with MyoD within the nucleus and Id1 exclusively in the cytoplasm. Cellular abundance of Id1 was markedly diminished from the very onset of muscle differentiation, whereas MyoD abundance was reduced to a much lesser extent and only at the later stages of differentiation. These reductions in MyoD and Id1 protein levels seem to result from a change in the rate of protein synthesis rather than the rate of degradation. In vivo protein stability studies revealed that the rates of ubiquitin-proteasome-mediated MyoD and Id1 degradation are independent of myogenic differentiation state. Id1 and MyoD were both rapidly degraded, each with a t½ ≃ 1 h in myoblasts and in myotubes. Furthermore, relative protein synthesis rates for MyoD and Id1 were significantly diminished during myoblast to myotube differentiation. These results provide insight as to the interaction between MyoD and Id1 in the process of muscle differentiation and have implications for the involvement of the ubiquitin-proteasome-mediated protein degradation and protein synthesis in muscle differentiation and metabolism under abnormal and pathological conditions. Mammalian skeletal myogenesis results in the differentiation of myoblasts to mature syncytial myotubes, a process regulated by an intricate genetic network of at least three protein families: muscle regulatory factors, E proteins, and Id proteins. MyoD, a key muscle regulatory factor, and its negative regulator Id1 have both been shown to be degraded by the ubiquitin-proteasome system. Using C2C12 cells and confocal fluorescence microscopy, we showed that MyoD and Id1 co-localize within the nucleus in proliferating myoblasts. In mature myotubes, in contrast, they reside in distinctive subcellular compartments, with MyoD within the nucleus and Id1 exclusively in the cytoplasm. Cellular abundance of Id1 was markedly diminished from the very onset of muscle differentiation, whereas MyoD abundance was reduced to a much lesser extent and only at the later stages of differentiation. These reductions in MyoD and Id1 protein levels seem to result from a change in the rate of protein synthesis rather than the rate of degradation. In vivo protein stability studies revealed that the rates of ubiquitin-proteasome-mediated MyoD and Id1 degradation are independent of myogenic differentiation state. Id1 and MyoD were both rapidly degraded, each with a t½ ≃ 1 h in myoblasts and in myotubes. Furthermore, relative protein synthesis rates for MyoD and Id1 were significantly diminished during myoblast to myotube differentiation. These results provide insight as to the interaction between MyoD and Id1 in the process of muscle differentiation and have implications for the involvement of the ubiquitin-proteasome-mediated protein degradation and protein synthesis in muscle differentiation and metabolism under abnormal and pathological conditions. Skeletal muscle differentiation is characterized by the terminal withdrawal of the myoblast from the cell cycle, activation of muscle-specific gene expression, and cell fusion into multinucleated myotubes. These events are coordinated by a family of four muscle-specific basic helix-loop-helix transcription factors, MyoD, Myf5, myogenin, and Mrf4, termed the muscle regulatory factors (1Puri P.L. Sartorelli V. J. Cell. Physiol. 2000; 185: 155-173Crossref PubMed Scopus (250) Google Scholar, 2Rudnicki M.A. Jaenisch R. BioEssays. 1995; 17: 203-209Crossref PubMed Scopus (365) Google Scholar, 3Yun K. Wold B. Curr. Opin. Cell Biol. 1996; 8: 877-889Crossref PubMed Scopus (318) Google Scholar, 4Pownall M.E. Gustafsson M.K. Emerson Jr., C.P. Annu. Rev. Cell Dev. Biol. 2002; 18: 747-783Crossref PubMed Scopus (457) Google Scholar). Mice lacking myogenin appropriately specify the skeletal muscle lineage but fail to terminally differentiate. Mrf4 is required for the maintenance of the differentiated myotubes. Although the specification of the myogenic lineage requires myoD and myf5, as double knock-out of both genes yields mice with no skeletal muscle (5Braun T. Arnold H.H. EMBO J. 1996; 15: 310-318Crossref PubMed Scopus (96) Google Scholar), MyoD is also required for healthy self-renewing proliferation of the adult skeletal muscle satellite cells (6Megeney L.A. Kablar B. Garrett K. Anderson J.E. Rudnicki M.A. Genes Dev. 1996; 10: 1173-1183Crossref PubMed Scopus (542) Google Scholar, 7Cooper R.N. Tajbakhsh S. Mouly V. Cossu G. Buckingham M. Butler-Browne G.S. J. Cell Sci. 1999; 112: 2895-2901Crossref PubMed Google Scholar, 8Zammit P.S. Golding J.P. Nagata Y. Hudon V. Partridge T.A. Beauchamp J.R. J. Cell Biol. 2004; 166: 347-357Crossref PubMed Scopus (665) Google Scholar). Muscle regulatory factors form heterodimers with ubiquitous E proteins and activate myogenic differentiation through their subsequent binding to specific sequences, termed E boxes, in the promoter regulatory regions of muscle-restricted target genes (4Pownall M.E. Gustafsson M.K. Emerson Jr., C.P. Annu. Rev. Cell Dev. Biol. 2002; 18: 747-783Crossref PubMed Scopus (457) Google Scholar). The transcriptional activities of muscle regulatory factors are negatively regulated by a family of inhibitors of DNA-binding (Id) proteins. The four Id proteins (Id1, Id2, Id3, and Id4) are helix-loop-helix proteins that contain no basic region and thus do not bind DNA. However, they are able to dimerize with one another and with MyoD or E proteins, albeit with different affinities (9Edmondson D.G. Olson E.N. J. Biol. Chem. 1993; 268: 755-758Abstract Full Text PDF PubMed Google Scholar, 10Benezra R. Rafii S. Lyden D. Oncogene. 2001; 20: 8334-8341Crossref PubMed Google Scholar, 11Langlands K. Yin X. Anand G. Prochownik E.V. J. Biol. Chem. 1997; 272: 19785-19793Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar). Id1 is most active in terms of MyoD binding. The binding affinity of Id1 for the E proteins is considerably higher than its affinity for MyoD. Sequestering the ubiquitous E proteins allows Id1 to control the transcriptional activity of muscle-specific MyoD. In cultured myoblasts, Id1 over-expression via a “dominant-negative” effect inhibits the transactivation by MyoD, thereby inhibiting the synthesis of proteins participating in muscle differentiation and consequently the fusion of myoblasts to myotubes (12Jen Y. Weintraub H. Benezra R. Genes Dev. 1992; 6: 1466-1479Crossref PubMed Scopus (393) Google Scholar). MyoD and Id1 have both been shown to be degraded by the ubiquitin-proteasome system (13Floyd Z.E. Trausch-Azar J.S. Reinstein E. Ciechanover A. Schwartz A.L. J. Biol. 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This pathway involves the activation of ubiquitin by the ubiquitin-activating enzyme, E1, followed by transfer of ubiquitin to E2, a ubiquitin-conjugating enzyme. E2 shuttles the ubiquitin to the substrate-specific ubiquitin ligase, E3, which then delivers the ubiquitin to the protein substrate to be degraded. The ubiquitin-proteasome proteolytic system is recognized as a versatile and efficient mechanism for the control of gene expression. The level of expression of MyoD and Id1 are vitally important during muscle differentiation. Both mRNA and protein levels of Id1 are down-regulated upon initiation of differentiation (20Benezra R. Davis R.L. Lockshon D. Turner D.L. Weintraub H. Cell. 1990; 61: 49-59Abstract Full Text PDF PubMed Scopus (1785) Google Scholar). MyoD mRNA levels change only slightly during differentiation (21Shimokawa T. Kato M. Ezaki O. Hashimoto S. Biochem. Biophys. Res. Commun. 1998; 246: 287-292Crossref PubMed Scopus (84) Google Scholar), yet the level of MyoD protein is decreased in reserve cells during muscle differentiation (22Yoshida N. Yoshida S. Koishi K. Masuda K. Nabeshima Y. J. Cell Sci. 1998; 111: 769-779Crossref PubMed Google Scholar). Reducing the level of MyoD protein by its destabilization has been shown to be associated with the inhibition of myogenic differentiation under abnormal or pathophysiological conditions. For example, accelerated MyoD degradation resulting from hypoxia blocked the accumulation of early myogenic differentiation markers such as myogenin, p21, and pRb and prevented both permanent cell cycle withdraw and terminal differentiation (23Di Carlo A. De Mori R. Martelli F. Pompilio G. Capogrossi M.C. Germani A. J. Biol. Chem. 2004; 279: 16332-16338Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). In inhibits myogenic differentiation through MyoD protein in a with skeletal muscle and to muscle S. J. S. J. 2004; PubMed Scopus Google Scholar, Jr., 2000; PubMed Scopus Google Scholar, M.C. J. 2004; 18: PubMed Scopus Google Scholar). in a cell that has a to that in myoblast from 1 muscle that C2C12 myogenic differentiation is by protein region via of MyoD protein levels J. Cell Biol. 2002; PubMed Scopus Google Scholar). studies in or in cells also that MyoD degradation is regulated by and Hatoum O. Gross-Mesilaty S. Breitschopf K. Hoffman A. Gonen H. Ciechanover A. Bengal E. Mol. Cell. Biol. 1998; 18: 5670-5677Crossref PubMed Google Scholar, A. M.A. Mol. Cell. Biol. 1998; 18: PubMed Scopus Google Scholar). of MyoD is required for its degradation. The specific to which MyoD MyoD degradation. which inhibits the binding of MyoD to the effect of the of MyoD. Furthermore, protein degradation studies of MyoD and Id1 to cells have shown that MyoD is able to both the and the degradation of Id1 J.S. Lingbeck J. Ciechanover A. Schwartz A.L. J. Biol. Chem. 2004; 279: 32614-32619Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). the and in myogenic differentiation the ubiquitin-proteasome-mediated degradation of MyoD and Id1 in muscle cells and their degradation and interaction to their abundance and thus differentiation. C2C12 myoblast cells are a characterized myogenic cell In the of they as an MyoD and differentiation of C2C12 cells be by which a of events with expression of myogenin as the cells withdraw from the cell cycle, proteins such as to and cell fusion then resulting in the of myotubes. Using C2C12 cells as we that MyoD and Id1 co-localize within the nucleus in proliferating myoblasts. In mature myotubes, in contrast, they reside in distinctive subcellular compartments, with MyoD within the nucleus and Id1 exclusively in the cytoplasm. Both MyoD and Id1 are rapidly degraded by the ubiquitin-proteasome pathway during the differentiation of myoblast to Furthermore, the rate of their degradation to be by the differentiation whereas a of MyoD and Id1 synthesis rate was during myogenic differentiation. and of MyoD in and Id1 in have been J.S. Lingbeck J. Ciechanover A. Schwartz A.L. J. Biol. Chem. 2004; 279: 32614-32619Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). Id1 with a differentiation at the was by the of the into Id1 DNA. were from was to Cell C2C12 myoblast cell was from the The cells were in and with and and in a at with differentiation was by the to differentiation and with and cells were then in differentiation for with of C2C12 myoblasts were the to the cells were with a with and in in and in of MyoD, myogenin, and in C2C12 myoblasts or myotubes was then by the and followed by with and the cells in and were with a and were with a control for the of MyoD and Id1 were by the with the and Id1 that were to the For double of MyoD and a with and the with are as were with a confocal with a during cells were with and at different stages of myogenic differentiation C2C12 myoblasts in C2C12 cells and the for the to 1 to C2C12 cells cultured in for 1 to of the cells were for at least in 1 1 and The cells were then and at for at to of each cell was by with an of cell of protein were in each by and were with and followed by with a were by control for MyoD were by the with to the of cells were with to protein The was with for and cells were and and cell were as with of each were in each for was in the as was for the of protein from the were the system and the were the degradation rate is as the for degradation of of the of the was by three to independent and is as of cells were with for and cells were and and cell were as with of each were in each for were in the as The for each were and that the of at was The of each were synthesis rates were the from of from to and from C2C12 myoblasts and differentiated myotubes were the was for MyoD, and system The Id1 are as and a of The MyoD and a of MyoD and Id1 degradation during muscle differentiation, we the C2C12 myoblast cells as (12Jen Y. Weintraub H. Benezra R. Genes Dev. 1992; 6: 1466-1479Crossref PubMed Scopus (393) Google Scholar, B. H. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar). C2C12 cells from to differentiation we were able to the of C2C12 myogenic differentiation, cell and fusion into multinucleated myotubes 1 in C2C12 cells were and but was no cell in of cells were to form multinucleated the the cell fusion rate was in of cells and a of syncytial cells were with of in These myotubes by cells and via fusion with myotubes and in in cells for to of the whereas a of cells as reserve cells (22Yoshida N. Yoshida S. Koishi K. Masuda K. Nabeshima Y. J. Cell Sci. 1998; 111: 769-779Crossref PubMed Google Scholar). The from myoblasts to myotubes was also by of a muscle with a for mature muscle was only in myotubes with cells studies have shown that MyoD subcellular markedly its degradation rate and that the degradation of Id1 be by MyoD J.M. Trausch-Azar J.S. Ciechanover A. Schwartz A.L. J. Biol. Chem. 2003; 278: 1817-1823Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 15Trausch-Azar J.S. Lingbeck J. Ciechanover A. Schwartz A.L. J. Biol. Chem. 2004; 279: 32614-32619Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). the of MyoD and Id1 degradation during differentiation and the interaction between we to the of MyoD and Id1 in C2C12 myoblasts and myotubes MyoD was to the cell nucleus in myoblasts as as in multinucleated myotubes. In myoblasts, Id1 was to be to the nucleus with MyoD, with level that they in In contrast, MyoD and Id1 to reside in distinctive subcellular in myotubes, with MyoD within the nucleus and Id1 exclusively in the cytoplasm. of the with its the for MyoD and Id1 in control not that the of both proteins in myoblasts and myotubes is not the result of binding. then MyoD and Id1 protein abundance during the of differentiation via Cellular abundance of Id1 is markedly diminished from the very onset of muscle differentiation, whereas MyoD abundance is reduced to a much lesser extent and only at the later stages of differentiation only in differentiation the Id1 protein level decreased to than of that in proliferating myoblasts. of differentiation, the MyoD protein level the not in differentiation Id1 protein was reduced whereas MyoD protein was reduced than the relative between MyoD and Id1 as the cells to differentiation. The abundance of the myogenic regulatory myogenin and the protein were also in the cell which terminal differentiation, the in differentiation cells also accumulation of from 1 These that the of muscle differentiation in a ubiquitin-proteasome-mediated degradation to the of MyoD and Id1 abundance during muscle differentiation, we their protein degradation in C2C12 myoblasts and myotubes. shown in MyoD was rapidly degraded in both with the ≃ of cells with a and of the markedly the rate of MyoD degradation For degradation was also both in myoblasts and in myotubes ≃ The of Id1 of results that both MyoD and Id1 are degraded by the ubiquitin-proteasome pathway during muscle differentiation and that the degradation rate is in myoblasts and in myotubes of the and only the MyoD the in was to the This is different from that in in which both of the MyoD not in are for the of MyoD degradation. that MyoD degradation requires its A. M.A. Mol. Cell. Biol. 1998; 18: PubMed Scopus Google and the to be much Although no change was in the degradation rate of MyoD or Id1 in myoblasts and myotubes the that MyoD or Id1 be degraded at a different rate at a specific between the onset of muscle differentiation and its thus MyoD and Id1 degradation rates at C2C12 differentiation. in MyoD, as as was degraded at the rate during differentiation from myoblasts to mature syncytial muscle These results that ubiquitin-proteasome-mediated MyoD and Id1 degradation is independent of the muscle differentiation state. in cells of MyoD and Id1 have that MyoD the rate of Id1 degradation J.S. Lingbeck J. Ciechanover A. Schwartz A.L. J. Biol. Chem. 2004; 279: 32614-32619Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). have shown that MyoD and Id1 co-localize in the nucleus of myoblasts that is interaction between the the relative abundance of MyoD or Id1 the degradation we MyoD or Id1 in myoblasts by the of MyoD or Id1 to myoblasts, each was rapidly degraded ≃ h for MyoD and t½ ≃ h for at the rate as was for MyoD or Id1 in C2C12 myoblasts Furthermore, with the degradation of the protein in each was to the of the Id1 protein to from the both and no in protein stability was for MyoD or Id1 during myogenic differentiation, we their protein synthesis rates in myoblasts and myotubes. of the and the rate of MyoD and Id1 the in which MyoD and Id1 protein degradation was the relative rate of MyoD and Id1 protein accumulation with the relative rates of protein synthesis in in in the rate of accumulation of both Id1 and MyoD was in myotubes than in myoblasts, that the rate of Id1 and MyoD protein synthesis is in myoblasts than in myotubes. the of the protein synthesis rates is a of myogenic differentiation, studies were also a of proteins. For we no in protein synthesis rate in myotubes myoblasts. For example, the relative synthesis rate of was in myoblasts and myotubes was degraded via the ubiquitin-proteasome system as of C2C12 cells with markedly not insight into the mechanism for the of protein synthesis rate of MyoD and we also their mRNA levels and differentiation results revealed a of Id1 mRNA level from myoblasts to myotubes, whereas no of MyoD mRNA level was for Id1 the of its level from myoblasts to myotubes with the in relative protein synthesis that is transcriptional for Id1 expression during myogenic differentiation. In the of MyoD, the in the relative protein synthesis rate in myoblasts and myotubes not to be to a in Muscle differentiation is a process and studies have shown that ubiquitin-proteasome-mediated protein degradation protein abundance by protein stability during muscle differentiation. For example, during myogenic differentiation of C2C12 the stability of with resulting in a of the protein G. S. J. S. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar). degradation of is for its during myogenic differentiation M. A. J. F. F. R. 2003; PubMed Scopus Google Scholar). MyoD, a key regulator of muscle differentiation, and its binding both during muscle differentiation, the are different In both MyoD and Id1 are degraded by the ubiquitin-proteasome system. that the rates of ubiquitin-proteasome-mediated MyoD and Id1 degradation to be independent of myogenic differentiation state. the in MyoD and Id1 protein levels during myogenic differentiation results from a change in the rate of protein synthesis rather than the rate of protein degradation. that the rate of ubiquitin-proteasome-mediated degradation of MyoD is not by the differentiation in in and MyoD from both myoblasts and myotubes in both and were by control with the that were for the of the MyoD not only the was for of the MyoD The for were studies have shown that is required for MyoD degradation A. M.A. Mol. Cell. Biol. 1998; 18: PubMed Scopus Google Scholar), with results that the MyoD is degraded the MyoD is of not we that different MyoD have different affinities the MyoD their state. the MyoD in upon the of the For example, one recognized the MyoD and thus in an for MyoD, thus the degradation rate that results from the degradation of the MyoD This is of in the of during muscle differentiation the relative abundance of the change during muscle differentiation. of the relative of the MyoD with from the differentiation was at the and the and not we that the of MyoD from to its between 1 and the early of the and then to its the at at which Although not the MyoD that of MyoD is important in MyoD studies of MyoD degradation into cells have shown that MyoD is to be and degraded J.M. Trausch-Azar J.S. Ciechanover A. Schwartz A.L. J. Biol. Chem. 2003; 278: 1817-1823Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). for of MyoD both in the MyoD in a network of transcriptional activities in C2C12 cells as as in cells of the muscle one for the of the MyoD to and subsequent ubiquitin-proteasome-mediated degradation is that is in the transcription process and is associated with or binding with has been shown that the of is by the specific to which MyoD and degradation of a MyoD protein that the DNA-binding are not Hatoum O. Gross-Mesilaty S. Breitschopf K. Hoffman A. Gonen H. Ciechanover A. Bengal E. Mol. Cell. Biol. 1998; 18: 5670-5677Crossref PubMed Google Scholar). of in MyoD to a the form of also significantly both the muscle transcriptional activity of MyoD and the of MyoD to myogenic of cells M. M. V. G. N. A. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar). These results that MyoD is to be the active results with MyoD degradation in C2C12 cells that MyoD is degraded at the rate as is during myogenic differentiation, the ubiquitin-proteasome system to the of MyoD abundance via with and MyoD results also that the ubiquitin-proteasome-mediated MyoD degradation and its of the muscle differentiation are important for muscle differentiation. of MyoD be a target for the differentiation under abnormal or pathological (23Di Carlo A. De Mori R. Martelli F. Pompilio G. Capogrossi M.C. Germani A. J. Biol. Chem. 2004; 279: 16332-16338Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, S. J. S. J. 2004; PubMed Scopus Google Scholar, M.C. J. 2004; 18: PubMed Scopus Google Scholar, J. Cell Biol. 2002; PubMed Scopus Google Scholar). that Id1 with MyoD to the nucleus in myoblasts, whereas in myotubes, Id1 exclusively to the cytoplasm. as a is to through N. M. Mol. Biol. Cell. 2002; PubMed Scopus Google Scholar). within the nucleus with MyoD that they with one another in with the of MyoD to Id1 to the nucleus J.S. Lingbeck J. Ciechanover A. Schwartz A.L. J. Biol. Chem. 2004; 279: 32614-32619Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). This result is also to the that from the to the nucleus with in cells S. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). the E protein the of its mechanism is for the of Id1 to the in myotubes, Id1 with higher affinity binding thus its in the of myotubes and from MyoD or muscle regulatory factors that muscle differentiation. For example, Id1 with proteins, which have a higher affinity than MyoD for These results thus in to the of its Id1 activity during muscle differentiation also be regulated by of Id1 via binding The implications of mechanism are as Id proteins have important in of basic helix-loop-helix transcription factors in the differentiation of cell and The involvement of Id1 with binding the of the of Id1 the Id protein as of Id1 and MyoD to cells and of and to cells S. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). In both Id protein is by its binding Id1 is one of the regulatory network in muscle differentiation, is to of the factors that to its Furthermore, by Id1 is that ubiquitin-proteasome-mediated degradation also the Id1 protein level during muscle differentiation. The of MyoD and Id1 protein abundance is for muscle differentiation, as of Id1 with its the for the initiation of MyoD transcriptional that during differentiation from myoblast to myotube the of Id1 and that of MyoD protein as is to a of the protein synthesis rate rather than a change of the protein degradation in the protein synthesis rate is not a of myoblast proteins during differentiation as no was for example, for the protein synthesis For its protein synthesis rate from myoblast to myotube with the of its mRNA that Id1 is regulated during muscle differentiation. For MyoD, the of change in its mRNA abundance that than transcriptional the results that protein abundance is regulated by the of protein synthesis and degradation during muscle differentiation, with different or the of specific protein muscle differentiation, MyoD and Id1 expression is to that of the E proteins and K. Yin X. Anand G. Prochownik E.V. J. Biol. 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