Myostatin gene (MSTN)

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Sequence Characterization of Coding  Regions of the Myostatin Gene (GDF8)  from Bakerwal Goats (Capra hircus) and  Comparison with the Sheep (Ovis aries)  Sequence

Sequence Characterization of Coding Regions of the Myostatin Gene (GDF8) from Bakerwal Goats (Capra hircus) and Comparison with the Sheep (Ovis aries) Sequence

Our result shows a high degree of conservation in Bakerwal goat myostatin compared to the ovine protein. The similarity and identity between the nucleotide and amino acid sequences from Ovis aries and Capra hircus were, as expected, high due to the close proximity of the species which belong to the same family Bovidae. Of the three alterations observed, none of the alteration could possibly represent a biological effect. Identifying mutations in sequences of myostatin gene using molecular techniques is an effective solution for the survey of double muscle phenotype and help the breeders to get important information in order to make the precise deci- sion for management and selecting the best population for reproduction and it lets the breeders to have a lot of data about genetic status of MSTN gene in livestock animals.
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SEQUENCE AND POLYMORPHISM ANALYSIS OF THE CAMEL (CAMELUS DROMEDARIUS) MYOSTATIN GENE

SEQUENCE AND POLYMORPHISM ANALYSIS OF THE CAMEL (CAMELUS DROMEDARIUS) MYOSTATIN GENE

camelids have peculiar evolutionary (and physiological) features. Interestingly, when compared to the available literature (Dahiya et al., 2014; Nagarajan et al., 2012, 2011; Du et al., 2009; Kacskovics et al., 2006), the sequence identity values observed for the MSTN gene between C. dromedarius and the other vertebrate species looks markedly higher, thus confirming previous evidences of the myostatin gene as a highly conserved gene across mammals. Further, to characterize the Camelus dromedarius MSTN gene in terms of sequence polymorphism, we sequenced a total of 22 animals from three different geographic regions (Algeria, Tunisia and Egypt). The results of the polymorphism analysis are represented in Table 1. As can be observed, we only detected three variant nucleotide sites, notably two transitions (798_G/A and 799_C/T) and one transversion (486_G/C). All the polymorphic sites were located in the first intron. Shah et al. (2006) screened a 256 bp region in the first exon of the Camelus dromedarius MSTN locus in 12 samples from six different Pakistani breeds without observing any sequence polymorphism. On the contrary, they found a C→T transition responsible for an Alanine to Valine amino acidic substitution when a 422 bp region of the first exon of the MYF5 gene was screened in the same animals. Vaccarelli et al. (2012) detected, at the T-cell receptor (TCR) gamma genes, SNPs with a frequency of one every 114 to 485 nucleotides, depending on the considered rearrangements, and somatic hypermutation was suggested on that locus as a mechanism to diversify the Camelus dromedarius
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A single nucleotide polymorphism in exon 3 of the myostatin gene in different breeds of domestic pigeon (Columba livia var  domestica)       32

A single nucleotide polymorphism in exon 3 of the myostatin gene in different breeds of domestic pigeon (Columba livia var domestica)       32

Myostatin gene polymorphism and its potential influence on various traits have been investigated in many species. In two Norwegian sheep breeds, two distinct MSTN gene mutations are linked to carcass conformation and obesity. SNPs were iden- tified in noncoding regulatory regions of the ovine and porcine MSTN gene. Some of them influence MSTN gene expression levels, which can be cor- related with growth, muscle mass and carcass per- formance traits (Dall’Olio et al. 2010). Zhang et al. (2011) discovered four substitutions (G2283A, C7552T, C7638T and T7661A) in the MSTN gene of the poultry breed, Bian. They reported that EE Figure 2. The results of DNA sequencing (heterozygotic ge- notype). The arrow indicates the SNP located in the 287 th
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The Myostatin Gene

The Myostatin Gene

The original study by McPherron et al. (1997) produced a lot of information regarding gross anatomical changes in homozygous myostatin knockout mice. These mice were almost 30% larger than controls and the mass was distributed throughout the body in increased skeletal muscle. The amount of weight increase in individual muscles correlated well with levels of myostatin expression in those muscles. Histological analysis revealed that the increase in muscle mass was due to both hyperplasia and hypertrophy, with the number of fibers increased by 86% and fiber size increased by 49%. Every study done since this original has documented similar increases in muscle size, such as that done by Mosher et al. (2007) examining whippets heterozygous for a myostatin mutation. Amthor, Otto, Macharia, McKinnell, and Patel (2006) noted increased muscle mass as well as some histological changes in muscle fiber composition in a myostatin deficient mouse line. Zebrafish also have a myostatin gene that results in increased muscle mass when knocked out (Xu, Wu, Zohar, and Du, 2003). Although the original studies in mice suggested an increase in muscle mass through both hyperplasia and hypertrophy, Yang et al. (2001) noted only an increase in hypertrophy with no significant hyperplasia. McCroskery, Thomas, Maxwell, Sharma, and Kambadur (2003) showed that myostatin decreased muscle stem cell activation, consistent with the hypothesis that myostatin deficiency leads to hyperplasia. A novel drug-inducible knockout was used to study the effects of post- developmental myostatin knockout by Welle, Bhatt, Pinkert, Tawil, and Thornton (2006). They engineered transgenic mice with a drug-inducible gene that expresses Cre recombinase and a form of the myostatin gene with loxP sites flanking one of the exons. After the mice reached
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Effect of propolis ethanol extract on myostatin gene expression and muscle morphometry of Nile tilapia in net cages.

Effect of propolis ethanol extract on myostatin gene expression and muscle morphometry of Nile tilapia in net cages.

When the results of muscle morphometry and myostatin gene expression are associated, the development of the white muscle in the Nile tilapia may be presumed to be related to a greater occurrence of hypertrophied muscle fibers and to myostatin increase throughout the life cycle of the fish. There was a greater recruitment of muscle fiber <30 mm (hyperplasia process) in the initial culture phases, coupled with a decrease at 105 days with a myostatin peak. When the inhibition of expression and activity of growth factors in muscle differentiation such as MyoD and myogeny by myostatin (Ruan et al., 2016) are taken into account, it may be supposed that these factors were suppressed throughout the experimental period at the same time as myostatin expression, causing a recruitment decrease of new fibers and a hypertrophic increase of muscle mass in the final phases of culture.
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Analysis of myostatin gene structure, expression and function in
zebrafish

Analysis of myostatin gene structure, expression and function in zebrafish

Myostatin (or GDF-8), a member of the Transforming Growth Factor-β (TGF-β) superfamily, was first identified in mice by McPherron et al. (1997) and has been demonstrated to negatively regulate skeletal muscle growth in several mammalian species. Myostatin knockout mice show a dramatic increase of skeletal muscle mass, and the increase results from a combination of hyperplasia and hypertrophy (McPherron et al., 1997). The ‘Double muscle’ breeds of cattle that have significantly more muscle mass than standard breeds were found to carry natural mutations in the myostatin gene (McPherron and Lee, 1997; Kambadur et al., 1997; Grobet et al., 1997, 1998). In vitro studies have demonstrated that Myostatin functions by inhibiting myoblast proliferation and differentiation (Thomas et al., 2000; Rios et al., 2001; Taylor et al., 2001; Langley et al., 2002). This is, in part, accomplished by downregulating myogenic gene expression (Langley et al., 2002; Amthor et al., 2002). The myostatin gene has been cloned from over 20 different vertebrate species including several fish species (McPherron and Lee, 1997; Rodgers and Weber, 2001; Rodgers et al., 2001; Maccatrozzo et al., 2001a,b, 2002; Kocabas et al., 2002; Roberts and Goetz, 2001;
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Soybean oil added to the diet reduces Myostatin gene expression in Longissimus dorsi muscle of sheep

Soybean oil added to the diet reduces Myostatin gene expression in Longissimus dorsi muscle of sheep

ABSTRACT. Myostatin is a protein involved in the regulation of myogenesis; animal meat quality can be influenced by its expression. Animals with low myostatin levels have increased muscle mass and are relatively stronger. We analyzed the influence of the addition of soybean, used soybean and palm oils to the diet on Myostatin gene expression in the Logissimus dorsi muscle of sheep reared in the Northeast Amazon region. A basic control diet was elaborated and used with the addition of 4% of the different oils. All animals were slaughtered at a weight of 35 kg and 5 g of Logissumus dorsi muscle was collected and RNA extracted, quantified and a RT-PCR was run. The control diet, without added oil, gave the highest Myostatin expression levels among all treatments. When unused soybean oil was added to the diet, it significantly decreased Myostatin expression and induced muscle hyperplasia, generating animals with greater musculature. The other oils did not significantly affect expresson of this gene.
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Molecular characterization, tissue expression and sequence variability of the barramundi (Lates calcarifer) myostatin gene

Molecular characterization, tissue expression and sequence variability of the barramundi (Lates calcarifer) myostatin gene

The central finding of this study is the identification of a miRNA target in the 3'UTR. MiRNA are small non-coding RNA (~22 nucleotide) that can actively regulate the expression of several genes at the post-transcriptional level by physical interaction with complementary mRNA sequences [41]. Sites presenting perfect complementarity at position 2–8 of the 5' end of the miRNA are likely to be targeted by the miRNA itself [42], but sites with one mis- match in the target sequence have also been considered as seeds [43]. Herein, a site located in the 3'UTR of LcMSTN- 1 and highly conserved across perciformes represents a putative target for the let-7 miRNA family. To support this finding, members of the let-7 family have been predicted, via evolutionary conservation, to interfere with the TGF-β signalling pathway [43]. To highlight the importance of gene expression regulation at the post-transcriptional level, a recent study has described a polymorphism in the 3'UTR of the sheep MSTN gene that generates an illegiti- mate new target site for two miRNAs [44]. This point mutation was statistically associated with an increased hypertrophy of muscle fibres, therefore defining a new class of regulatory mutations. The homologous site of interaction, herein described for the first time in finfish, represents a possible valuable target for the identification of fast growing haplotypes. Further, miRNAs may also play a pivotal developmental role inhibiting the transla- tion of MSTN in lower vertebrates in a tissue-specific man- ner.
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Myostatin gene promoter: structure, conservation and importance as a target for muscle modulation

Myostatin gene promoter: structure, conservation and importance as a target for muscle modulation

The orange-spotted grouper (Epinephelus coioides) displays a TATA and CAAT boxes at positions − 18 and − 66 bp, respectively, as well as ten potential E-boxes in a fragment of approximately 1.9 kb of the 5′ region of stn-1 [87]. Other myogenic binding sites were also iden- tified, such as MEF2, MTBF and GFI-1B, as summarized in Additional file 1. A series of deletions were used to determine the role of each E-box, and showed that the presence of E5 significantly decreased promoter activity, as indicated by luciferase assays, both in vitro and in vivo [87]. Promoter activity was again elevated in the presence of E6, which displayed an antagonistic role to E5. MYOD was shown to be the main binder and acti- vator of E6. mstn-1 promoter activity was also investi- gated using a pEGFP-1 reporter vector which was co- transfected into grouper cells (GF-1), and was shown to be downregulated upon treatment with nodavirus, a member of the Betanodavirdae family, the causative agent of viral nervous necrosis or fish encephalitis. This might be the reason why naturally infected groupers show MSTN protein downregulation. On the other hand, infection with the nervous necrosis virus (NNV) significantly induced mstn promoter activity, indicating a possible role in immune response [87].
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Suppression of body fat accumulation in myostatin deficient mice

Suppression of body fat accumulation in myostatin deficient mice

Myostatin is a TGF- β family member that acts as a negative regulator of muscle growth. Mice lack- ing the myostatin gene (Mstn) have a widespread increase in skeletal muscle mass resulting from a combination of muscle fiber hypertrophy and hyperplasia. Here we show that Mstn-null mice have a significant reduction in fat accumulation with increasing age compared with wild-type littermates, even in the setting of normal food intake (relative to body weight), normal body temperature, and a slightly decreased resting metabolic rate. To investigate whether myostatin might be an effective tar- get for suppressing the development of obesity in settings of abnormal fat accumulation, we analyzed the effect of the Mstn mutation in two genetic models of obesity, agouti lethal yellow (A y ) and obese
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Myostatin and its precursor protein are increased in the skeletal muscle of patients with Type-II muscle fibre atrophy

Myostatin and its precursor protein are increased in the skeletal muscle of patients with Type-II muscle fibre atrophy

Mstn is a secreted protein considered a normal neg- ative regulator of muscle growth during develop- ment and of muscle mass during adulthood [13]. In mouse models, knocking out the Mstn gene and overexpressing proteins neutralising Mstn caused an increase in muscle mass [13]. In cattle and whippet dogs naturally-occurring myostatin gene mutations led to significantly increased muscle size [26, 28]. A child with a homozygous Mstn gene mutation that results in reduced production of Mstn protein was reported increased muscle bulk and strength [35]. Conversely, mature Mstn protein was report- ed to have increased in the muscle tissue of pa- tients with HIV-associated muscle wasting [14], and increased MstnPP mRNA was reported in muscle wasting associated with osteoarthritis [31] (these conditions are associated with Type-II fibre atro- phy [Engel and Askanas, unpublished]). However, in some studies, Mstn gene-knockout mice or mice carrying Mstn gene mutations had muscle weakness, mitochondria depletion and tubular aggregates, de- spite their larger muscle mass [1]. Previously, the question was raised as to whether the larger mus- cle is better [15].
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Mapping a Syntenic Modifier on Mouse Chromosome 1 Influencing the Expressivity of the Compact Phenotype in the Myostatin Mutant (MstnCmpt-dl1Abc) Compact Mouse

Mapping a Syntenic Modifier on Mouse Chromosome 1 Influencing the Expressivity of the Compact Phenotype in the Myostatin Mutant (MstnCmpt-dl1Abc) Compact Mouse

regulating MyoD expression. J. Biol. Chem. 277: 49831–49840. We thank So´va´ri Krisztina and Galli Gyo¨rgyne´ for their excellent McPherron, A. C., and S.-J. Lee, 1997 Double muscling in cattle technical assistance. This research was supported by grant no. T043409 due to mutations in the myostatin gene. Proc. Natl. Acad. Sci. from Hungarian Scientific Research Fund (OTKA). USA 94: 12457–12461.

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Preliminary Investigation into a Potential Role for Myostatin and Its Receptor (ActRIIB) in Lean and Obese Horses and Ponies

Preliminary Investigation into a Potential Role for Myostatin and Its Receptor (ActRIIB) in Lean and Obese Horses and Ponies

Work in murine models and humans has identified that myostatin may have an important role in obesity development. Myostatin knock-out (KO) mice offered high-fat diets are resistant to gains in body fat [14,15], and although this effect may be secondary to the increases in lean body mass, myostatin had direct effects on adipocyte differentiation [16,17]. Furthermore, blocking myostatin increased the functional capacity of brown adipose tissue (BAT) [18] and may even drive the browning of white adipose tissue through the up-regulation of BAT-specific genes [19]. Myostatin gene expression was positively associated with obesity in both mouse [20] and human studies [21], whilst blocking myostatin function in mature mice elicited positive effects on glucose and insulin dynamics [22]. In comparison to human and rodent studies, there are fewer studies of myostatin in horses and ponies, and the extant reports generally focus on the identification of a number of single nucleotide polymorphisms (SNP’s) in the myostatin gene. SNPs have been associated with different attributes including breeds of different morphological type [23], optimal race distance in Thoroughbred horses [24] and skeletal muscle fibre type proportions in Quarter horses [25].
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Expression profiles of myostatin and calpastatin genes and analysis of shear force and intramuscular fat content of yak longissimus muscle

Expression profiles of myostatin and calpastatin genes and analysis of shear force and intramuscular fat content of yak longissimus muscle

tease (Barnoy et al., 1997). Garikipati et al. (2006) reported the widespread expression of MSTN in over twenty tissues of rainbow trout and especially high level in spleen and eyes. In the present experi- ment, the expression of MSTN was also observed in all tissues examined. It is reported that the inhibi- tion of MSTN in muscle and adipose tissue has a different influence on the fat mass of mouse (Guo et al., 2009), thus the expression pattern of MSTN might be linked to their tissue-specific functions. The lower level of both MSTN and CAST in the longissimus muscle of yak calf relative to adult yak (Figure 2) might imply that the longissimus muscle growth is less inhibited in yak calf compared to adult yak, which is in accordance with the faster growth rate of young animals. In this study we also observed that the longissimus muscle of adult yak contained a lower mRNA level of MSTN than in cattle and a similar level of CAST. Because both MSTN and CAST are negative regulators of skeletal muscle growth (Barnoy et al., 1997; Lee, 2004), we therefore suggest that MSTN and CAST in long- issimus muscle at least are not key factors affecting the body size of yak (smaller than that of cattle). In addition, we observed a high level of CAST in yak heart and spleen (Figure 1). This might be related to the control of the normal structure and function of heart and spleen by preventing the uncontrolled ac- tivity of Ca 2+ -dependent protease (Kar et al., 2007).
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Significance of serum Myostatin in hemodialysis patients

Significance of serum Myostatin in hemodialysis patients

For each patient we collected: i) clinical data, in- cluding age, dialysis modality, dialysis vintage and body mass index (BMI), and ii) biochemical data, such as pre-dialysis potassium, phosphate, transfer- rin, albumin, and C-reactive protein (CRP) serum levels. McAuley index (McA) = exp. [2.63–0.28 ln (in- sulin in mU/l) – 0.31ln (triglycerides in mmol/l)] was used to define insulin resistance (IR), consider- ing a diagnostic cut-off point of ≤5.8 [15]. Serum Mstn level was tested by ELISA (Quantikine; R&D Systems, Minneapolis, MN, USA; detection limit 5.3 pg/ml), at the beginning and at the end of the hemodialysis session.
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Dual exon skipping in myostatin and dystrophin for Duchenne muscular dystrophy

Dual exon skipping in myostatin and dystrophin for Duchenne muscular dystrophy

To examine the feasibility to induce myostatin exon 2 skipping, different concentrations of each AON were transfected into the myotube cultures using the cationic polymer polyethylenimine (PEI). More than 80% of the cells showed specific nuclear uptake upon transfection with 5’-fluorescein (FAM)-labeled control AON (Figure 2A). RT-PCR performed two days post transfection (Fig- ure 2B) and subsequent sequencing analysis (Figure 2C) showed the exclusion of exon 2 from the myostatin transcript in the myostatin AON-transfected cells, resulting in a premature stop codon formation. This internally truncated fragment was not observed in any of the non-transfected and control AON-transfected myotubes. One myostatin AON, namely AON1, gave the most consistent and highest skipping efficiency [Additional file 1]. Thus we further used the AON1 (addressed as myostatin AON from now on) and con- firmed its exon skipping ability in human and to a lower extent in mouse cells models, using its perfect comple- mentary to the human and mouse MSTN sequences (Figure 2B and not shown).
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Negative auto-regulation of myostatin expression is mediated by Smad3 and MicroRNA-27

Negative auto-regulation of myostatin expression is mediated by Smad3 and MicroRNA-27

) or with CMM in the absence (0.05% DMSO) or presence of SIS3 (10 mM) for 24 h prior to assessment of luciferase activity. All luciferase activity was normalized to Renilla luciferase and expressed as fold change relative to respective controls (CCM+DMSO). Bars represent mean values 6 S.E.M (n = 3). p,0.05 (*), p,0.01 (**) and p,0.001 (***). (D) Assessment of pMIR-REPORT TM luciferase activity in C2C12 myoblasts co- transfected with Mstn 39UTR and either AntagomiR Neg, AntagomiR-27a or AntagomiR-27b in the absence (2) or presence (+) of CMM. Bars represent mean values 6 S.E.M (n = 3). p,0.001 (***). (E) Assessment of pMIR-REPORT TM luciferase activity in C2C12 myoblasts co-transfected with Mstn 39UTR- mut and either AntagomiR Neg, AntagomiR-27a or AntagomiR-27b in the absence (2) or presence (+) of Mstn protein (CMM). Bars represent mean values 6 S.E.M (n = 3). All luciferase activity was normalized to Renilla luciferase and expressed as fold change relative to control (CMM - and AntagomiR Neg +). (F) Based on the data presented in this current manuscript we propose that upon Mstn-mediated receptor activation Smad3 up- regulates the expression of miR-27a/b, which in turn leads to reduced Mstn expression and impaired Mstn function, thus forming the basis of a novel negative Mstn auto-regulatory loop in muscle.
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The Effect of Hyperammonemia on Myogenesis in Broiler Embryos.

The Effect of Hyperammonemia on Myogenesis in Broiler Embryos.

The embryonic environment is crucial to myogenesis and ultimately determines maximum potential skeletal muscle growth. The process of somatic progenitor cells becoming specified myoblasts, and subsequently differentiated myocytes is intricately controlled by Pax genes, myogenic regulatory factors, and inhibitors, such as myostatin. Initially expressed are the primary myogenic regulatory factors, myogenic factor 5 (MyF5) and myogenic determination factor 1 (MyoD), which are responsible for the commitment of somatic progenitor cells to become myoblasts (Rudnicki et al., 1993; Rudnicki et al., 1993). Without expression of Pax-3, the migration of somatic progenitor cells to the developing limb buds does not occur, and is therefore essential to skeletal muscle growth (Tajbakhsh et al., 1997). The secondary myogenic regulatory factors, myogenin and myogenic regulatory factor 4 (MRF4) are responsible for myoblast differentiation and maturation of myocytes, which are the functional units of mature muscles. This process, which only occurs in the developing embryo, determines the number of mature muscle fibers present in the adult animal. Post-natal muscle growth relies on an increase in myofiber size, or hypertrophy.
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Myostatin signals through miR-34a to regulate Fndc5 expression and browning of white adipocytes

Myostatin signals through miR-34a to regulate Fndc5 expression and browning of white adipocytes

not only in an endocrine manner but also through an autocrine pathway. In addition, we further show that both antibody- mediated neutralization of Irisin in Mstn − / − white adipocytes is able to signi fi cantly decrease the elevated expression of ucp1 and additional BAT marker genes (cox7a1, ebf3, hspb7 and cidea) observed in Mstn − / − adipocytes when compared with control (Figure 5b). A similar reduction in ucp1 expression was noted upon siRNA-mediated inhibition of Fndc5 expression in Mstn − / − adipocytes (Figures 5c and d). However, it is noteworthy to mention that antibody-mediated neutralization of Irisin was not able to completely reduce the increased ucp1 expression in Mstn − / − adipocytes, to the same level in WT adipocytes (Figure 5b). We therefore speculate that additional factors, other than Irisin may contribute to the enhanced browning and thermogenic gene expression observed in Mstn − / − white adipo- cytes. As FGF21 signaling is also targeted by miR-34a, and given the reduced miR-34a expression in Mstn −/ − adipocytes (Figure 4b), it is likely that enhanced FGF21 signaling may also promote browning of Mstn −/ − adipocytes. However, further studies will need to be performed to assess the expression of other miR-34 targets including FGF21 receptor components in Mstn − / − adipocytes. In addition to FGF21, we have previously shown that the loss of Mstn promotes the browning of WAT through a mechanism involving COX-2. 11 Given the fact that COX-2 can promote the expression of ucp1 and induce browning of WAT, 17 it is quite possible that enhanced COX-2 expression may also contribute to the elevated ucp1 expression observed in Mstn − / − adipocytes.
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Polymorphism and expression of some myogenic genes at embryonic stages and 37 days age of cobb broiler chickens and their impact on the marketing weights

Polymorphism and expression of some myogenic genes at embryonic stages and 37 days age of cobb broiler chickens and their impact on the marketing weights

Results: The expression profile of MSTN and MyoG at different embryonic stages showed the highest significant increase at day 7 (125±0.06, 25±0.99 fold), and their expression decrease at E13, 16 and 3 days post hatch. The relative expression level of MyoD was significantly high (p≤ 0.05) at E7 (42.79±2.03 fold) and reach its peak at E16 (54.95±2.92 fold) and decreased to 6.80±1.30 fold at three days post hatch. At marketing age, there were differences in expression level of MSTN, MyoD, and MyoG in Cobb broiler among high and low body weight birds. Concerning MSTN gene sequence data; high similarity in the sequences was detected among high and low body weights at the three exons of Cobb broiler.
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