Disease relevance of Myod1

• To evaluate the potential interplay between MyoD and IGF signaling pathways, we have studied muscle differentiation in C3H 10T1/2 fibroblasts acutely converted to myoblasts by quantitative infection with a recombinant adenovirus encoding mouse MyoD [1].
• Our study revealed a novel anti-differentiation effect exerted by hypoxia in myogenic cells and identified MyoD degradation as a relevant target of hypoxia [2].
• Thus we propose that myostatin plays a critical role in myogenic differentiation and that the muscular hyperplasia and hypertrophy seen in animals that lack functional myostatin is because of deregulated proliferation and differentiation of myoblasts [3].
• The involvement of proteasome in myogenic differentiation of murine myocytes and human rhabdomyosarcoma cells [4].
• Mice lacking both MyoD and dystrophin displayed a marked increase in severity of myopathy leading to premature death, suggesting a role for MyoD in muscle regeneration [5].

Psychiatry related information on Myod1

• Thus, ILK likely influences the initial decision making process of myogenic differentiation by regulation of MAP kinase activation [6].
• In murine myogenic cells the HLH network includes multiple members of the E protein, MyoD, and Id families; changes in the network characterize muscle determination and differentiation and have been proposed as causal for these developmental transitions [7].

High impact information on Myod1

• The myogenic determination factor, MyoD (encoded by Myod1), is a target of the differentiation checkpoint in myoblasts [8].
• A myogenic differentiation checkpoint activated by genotoxic stress [8].
• MyoD is a muscle-specific regulator able to induce myogenesis in numerous cell types [9].
• Our results demonstrate that SWI/SNF enzymes promote MyoD-mediated muscle differentiation and indicate that these enzymes function by altering chromatin structure in promoter regions of endogenous, differentiation-specific loci [9].
• Therefore, Pax-3 and Myf-5 define two distinct myogenic pathways, and MyoD acts genetically downstream of these genes for myogenesis in the body [10].

Chemical compound and disease context of Myod1

• Here, we show that differentiation of C2BP5 myoblasts could be induced in the absence of IGF action by recombinant adenoviruses expressing MyoD or myogenin, but it was reversibly impaired by the PI3-kinase inhibitor LY294002 [11].
• It has been demonstrated that the adenovirus E1A gene products inhibit myogenic differentiation in the mouse C2 muscle cell line [12].

Biological context of Myod1

• The difference in the species origin of genes from this region of chromosome 7 may underlie the basis of the antigenicity of the minor histocompatibility antigen H4, defined by the strain B10.129(21M), and may account for the enhanced Myod1 activity observed in SJL/J mice [13].
• Muscle LIM protein, a novel essential regulator of myogenesis, promotes myogenic differentiation [14].
• To understand how the skeletal muscle lineage is induced during vertebrate embryogenesis, we have sought to identify the regulatory molecules that mediate induction of the myogenic regulatory factors MyoD and Myf-5 [15].
• Inactivation of MyoD in mice leads to up-regulation of the myogenic HLH gene Myf-5 and results in apparently normal muscle development [16].
• Normally, Myf-5 expression becomes markedly reduced at day 12 of gestation when MyoD mRNA first appears [16].

Anatomical context of Myod1

• Our results indicate that MyoD is dispensable for skeletal muscle development in mice, revealing some degree of functional redundancy in the control of the skeletal myogenic developmental program [16].
• Under conditions that normally induce differentiation, MyoD-/- cells continued to proliferate and with delayed kinetics yielded reduced numbers of predominantly mononuclear myocytes [17].
• In trunk somites, however, MyoD is initially expressed in ventral cells [18].
• Identification of novel MyoD gene targets in proliferating myogenic stem cells [19].
• Treatment with bone morphogenetic protein 2 (BMP-2) not only blocks myogenic differentiation of C2C12 cells but also induces osteoblast differentiation [20].

Associations of Myod1 with chemical compounds

• Over-expression of MLP in C2 myoblasts potentiates myogenic differentiation and reduces its sensitivity to TGF beta [14].
• Deletion mutagenesis of the MyoD protein demonstrated that the ability to activate endogenous genes depended on two regions: a region rich in cysteine and histidine residues between the acidic activation domain and the bHLH domain, and a second region in the carboxyl terminus of the protein [21].
• MyoD induces myogenic differentiation through cooperation of its NH2- and COOH-terminal regions [22].
• Herculin, a fourth member of the MyoD family of myogenic regulatory genes [23].
• Betaglycan expression is transcriptionally up-regulated during skeletal muscle differentiation. Cloning of murine betaglycan gene promoter and its modulation by MyoD, retinoic acid, and transforming growth factor-beta [24].

Physical interactions of Myod1

• (iv) Addition of p204 overcame the inhibition by the Id proteins of the binding of MyoD and E47 to DNA in vitro [25].
• The proximal promoter of the Barx2 gene contained binding sites for several factors involved in myoblast differentiation including MyoD, myogenin, serum response factor, and myocyte enhancer factor 2 [26].
• These findings demonstrate that M-Twist interacts with MyoD through the basic domains, thereby inhibiting MyoD [27].
• Congruent with a role for Smad7 in myogenesis, we observed that the muscle regulatory factor (MyoD) binds to and transactivates the Smad7 proximal promoter region [28].
• MyoD targets chromatin remodeling complexes to the myogenin locus prior to forming a stable DNA-bound complex [29].

Enzymatic interactions of Myod1

• Notch1 signals were measured by both the activation of the hairy/enhancer of split (HES1) promoter and by the antagonism of MyoD-induced muscle creatine kinase (MCK) promoter activity [30].
• Comparative two-dimensional tryptic phosphopeptide mapping combined with site-directed mutagenesis revealed that Mos phosphorylates MyoD on serine 237 [31].

Regulatory relationships of Myod1

• This suggests that Myf-5 expression is repressed by MyoD [16].
• In vertebrates, Notch activation has been shown to block MyoD activation and muscle differentiation in vitro, suggesting that this pathway may act to maintain the cells in an undifferentiated proliferative state [32].
• Co-transfection of MyoD together with an activated form of MEF2C containing the Herpesvirus VP16 transcriptional activation domain partially bypasses the requirement for pRb and induces late muscle-gene expression in replicating cells [33].
• In vitro, increasing concentrations of recombinant mature myostatin reversibly blocked the myogenic differentiation of myoblasts, cultured in low serum media [3].
• The homeodomain protein Barx2 promotes myogenic differentiation and is regulated by myogenic regulatory factors [26].
• As such, the MyoD enhancer SMB element is the site for a molecular relay where MyoD expression is first initiated in activated satellite cells in an SRF-dependent manner and then increased and maintained by MEF2 binding in differentiated myotubes [34].

Other interactions of Myod1

• Redefining the genetic hierarchies controlling skeletal myogenesis: Pax-3 and Myf-5 act upstream of MyoD [10].
• The number of MyoD- and Myogenin-expressing activated satellite cells after injury were significantly reduced in mutants [35].
• RNA analysis revealed an up-regulation of MyoD mRNA in mdx but not in FGF-6(-/-)/mdx double mutant mice [35].
• Here we show that p38 MAPK, whose activity is essential for myogenesis, regulates MyoD/E47 heterodimerization [36].
• A natural hepatocyte growth factor/scatter factor autocrine loop in myoblast cells and the effect of the constitutive Met kinase activation on myogenic differentiation [37].

Analytical, diagnostic and therapeutic context of Myod1

• We have used microarray and polymerase chain reaction approaches to measure the induction of muscle gene expression by MyoD and Myf5 in an in vitro model [22].
• We have taken advantage of the chick model to investigate the effect of electroporation of the mouse Myf5 and MyoD genes in the embryonic neural tube [38].
• MyoD enhances BMP7-induced osteogenic differentiation of myogenic cell cultures [39].
• Sequence analysis of 976 bp 5' flanking region revealed several potential cis-acting elements: 1) Three E boxes (MyoD binding sites), namely, E1, E2 and E3, located at -79, -832 and -936, respectively; 2) one MEF2 binding site at -864; 3) a region with homology to M-CAT motif at -587; 4) several GC boxes [40].
• In situ hybridization analysis revealed that MyoD expression was the most widespread and was expressed in satellite cells and small regenerating muscle fibers surrounding necrotic fibers [41].

References