Effects of Different Generations and Sex on Physiological, Biochemical, and Growth Parameters of Crossbred Beef Cattle by Myostatin Gene-Edited Luxi Bulls and Simmental Cows
Chao HaiChunling BaiLei YangZhuying WeiHong WangHaoran MaHaibing MaYuefang ZhaoGuanghua SuGuangpeng Li
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(1) Background: Myostatin (MSTN) is a protein that regulates skeletal muscle development and plays a crucial role in maintaining animal body composition and muscle structure. The loss-of-function mutation of MSTN gene can induce the muscle hypertrophic phenotype. (2) Methods: Growth indexes and blood parameters of the cattle of different months were analyzed via multiple linear regression. (3) Results: Compared with the control group, the body shape parameters of F2 cattle were improved, especially the body weight, cross height, and hip height, representing significant development of hindquarters, and the coat color of the F2 generation returned to the yellow of Luxi cattle. As adults, MSTN gene-edited bulls have a tall, wide acromion and a deep, wide chest. Both the forequarters and hindquarters are double-muscled with clear muscle masses. The multiple linear regression demonstrates that MSTN gene-edited hybrid beef cattle gained weight due to the higher height of the hindquarters. Significant differences in blood glucose, calcium, and low-density lipoprotein. Serum insulin levels decreased significantly at 24 months of age. MSTN gene editing improves the adaptability of cattle. (4) Conclusions: Our findings suggest that breeding with MSTN gene-edited Luxi bulls can improve the growth and performance of hybrid cattle, with potential benefits for both farmers and consumers.Keywords:
Myostatin
Beef Cattle
Myostatin, a TGF‐β family member, is a negative regulator of muscle growth. Here, we generated transgenic mice that expressed myostatin mutated at its cleavage site under the control of a muscle specific promoter creating a dominant negative myostatin. These mice exhibited a significant (20–35%) increase in muscle mass that resulted from myofiber hypertrophy and not from myofiber hyperplasia. We also evaluated the role of myostatin in muscle degenerative states, such as muscular dystrophy, and found significant downregulation of myostatin. Thus, further inhibition of myostatin may permit increased muscle growth in muscle degenerative disorders.
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Regulation of the Myostatin Protein in Overload-Induced Hypertrophied Rat Skeletal Muscle Paige A. Affleck Department of Exercise Sciences, BYU Master of Science Myostatin (GDF-8) is the chief chalone in skeletal muscle and negatively controls adult skeletal muscle growth. The role of myostatin during overload-induced hypertrophy of adult muscle is unclear. We tested the hypothesis that overloaded adult rodent skeletal muscle would result in reduced myostatin protein levels. Overload-induced hypertrophy was accomplished by unilateral tenotomy of the gastrocnemius tendon in male adult Sprague-Dawley rats followed by a two-week period of compensatory overload of the plantaris and soleus muscles. Western blot analysis was performed to evaluate changes in active, latent and precursor myostatin protein levels. Significant hypertrophy was noted in the plantaris (494 ± 29 vs. 405 ± 15 mg, p < 0.05) and soleus (289 ± 12 vs. 179 ± 37 mg, p < 0.05) muscles following overload. Overloaded soleus muscle decreased the concentration of active myostatin protein by 32.7 ± 9.4% (p < 0.01) while the myostatin precursor protein was unchanged. Overloaded plantaris muscle decreased the concentration of active myostatin protein by 28.5 ± 8.5% (p < 0.01) while myostatin precursor levels were reduced by 17.5 ± 5.9% (p < 0.05). Myostatin latent complex concentration decreased in the overloaded soleus and plantaris muscle by 15.0 ± 5.9% and 70.0 ± 2.3% (p < 0.05), respectively. These data support the hypothesis that the myostatin signaling pathway in overloaded muscles is generally downregulated and contributes to muscle hypertrophy. Plasma concentrations of total and active myostatin proteins were similar in overloaded and control animals and averaged 8865 ± 526 pg/ml and 569 ± 28 pg/ml, respectively. Tissue levels of BMP1, an extracellular proteinase that converts myostatin to its active form, also decreased in overloaded soleus and plantaris muscles by 40.4 ± 12.9% and 32.9 ± 6.9% (p < 0.01), respectively. These data support the hypothesis that local, rather than systemic, regulation of myostatin contributes to the growth of individual muscles, and that an association exists between the extracellular matrix proteinase BMP-1 and the amount of active myostatin in overloaded muscles.
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Key points Myostatin is an important regulator of muscle mass and a potential therapeutic target for the treatment of diseases and injuries that result in muscle atrophy. Targeted genetic mutations of myostatin have been generated in mice, and spontaneous loss‐of‐function mutations have been reported in several species. The impact of myostatin deficiency on the structure and function of muscles has been well described for mice, but not for other species. We report the creation of a genetic model of myostatin deficiency in rats using zinc finger nuclease technology. The main findings of the study are that genetic inactivation of myostatin in rats results in increases in muscle mass without a deleterious impact on the specific force production and tendon mechanical properties. The increases in mass occur through a combination of fibre hypertrophy, hyperplasia and activation of the insulin‐like growth factor‐1 pathway, with no substantial changes in atrophy‐related pathways. This large rodent model has enabled us to identify that the chronic loss of myostatin is void of the negative consequences to muscle fibres and extracellular matrix observed in mouse models. Furthermore, the greatest impact of myostatin in the regulation of muscle mass may not be to induce atrophy directly, but rather to block hypertrophy signalling. Abstract Myostatin is a negative regulator of skeletal muscle and tendon mass. Myostatin deficiency has been well studied in mice, but limited data are available on how myostatin regulates the structure and function of muscles and tendons of larger animals. We hypothesized that, in comparison to wild‐type ( MSTN +/+ ) rats, rats in which zinc finger nucleases were used to genetically inactivate myostatin ( MSTN Δ/Δ ) would exhibit an increase in muscle mass and total force production, a reduction in specific force, an accumulation of type II fibres and a decrease and stiffening of connective tissue. Overall, the muscle and tendon phenotype of myostatin‐deficient rats was markedly different from that of myostatin‐deficient mice, which have impaired contractility and pathological changes to fibres and their extracellular matrix. Extensor digitorum longus and soleus muscles of MSTN Δ/Δ rats demonstrated 20–33% increases in mass, 35–45% increases in fibre number, 20–57% increases in isometric force and no differences in specific force. The insulin‐like growth factor‐1 pathway was activated to a greater extent in MSTN Δ/Δ muscles, but no substantial differences in atrophy‐related genes were observed. Tendons of MSTN Δ/Δ rats had a 20% reduction in peak strain, with no differences in mass, peak stress or stiffness. The general morphology and gene expression patterns were similar between tendons of both genotypes. This large rodent model of myostatin deficiency did not have the negative consequences to muscle fibres and extracellular matrix observed in mouse models, and suggests that the greatest impact of myostatin in the regulation of muscle mass may not be to induce atrophy directly, but rather to block hypertrophy signalling.
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Increasing size and strength of skeletal muscle represents a promising therapeutic strategy for muscular disorders. One possible new tool is Myostatin (Mstn) because it plays a crucial role in regulating skeletal muscle mass. The first goal of our work was to determine whether Mstn inhibition could prevent muscle atrophy in catabolic states. As glucocorticoids play a major role in most muscle atrophy models, we assessed whether muscle atrophy caused by glucocorticoids in excess could be prevented by Mstn inhibition. This hypothesis was suggested by the fact that glucocorticoids increase muscle Mstn expression and that Mstn muscle overexpression is sufficient to cause muscle atrophy. Our work showed that deletion of Mstn gene protects skeletal muscle from glucocorticoid-induced atrophy, partially through inhibition of proteolysis. The identification of Mstn binding proteins able to inhibit Mstn activity has led to potential new approaches for postdevelopmental muscle mass enhancement. These Mstn binding proteins include Follistatin (FS) which shows a potent Mstn-inhibiting activity. The increase in muscle mass observed in transgenic mice overexpressing FS in muscle is even significantly larger than that observed in Mstn KO mice, suggesting that other ligands could contribute to the muscle hypertrophic effect of FS. The mechanisms involved in the FS effect are however relatively unknown. The second aim of this thesis was to investigate the contribution of satellite cells to the FS-induced muscle hypertrophy and to assess whether other FS ligands could act similarly to Mstn in controlling muscle growth. Our study showed that FS overexpression induces skeletal muscle hypertrophy via satellite cell activation and probably increased protein synthesis. Furthermore, our results indicate that FS-induced hypertrophy results not only from Mstn but also from Act inhibition. These observations therefore suggest that, besides Mstn, Act is a crucial player in the regulation of muscle mass. In conclusion, this work demonstrates the interest and the feasibility of Mstn inhibition as a potential therapeutic approach in muscle wasting disease. Since Mstn gene deletion prevents the muscle atrophy caused by dexamethasone and glucocorticoids are involved in muscle atrophy observed in many catabolic conditions, Mstn inhibition may be helpful in the treatment of disease-related muscle loss. Among Mstn inhibitors, FS seems to be a promising tool because of its powerful hypertrophic effect on skeletal muscle mass. As we showed, its anabolic action results from inhibition of both Mstn and Act, which negatively regulate muscle growth.
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An increase in muscle mass requires a positive state of muscle net protein balance. Such a state can be achieved by changes, either separately or together, in muscle protein synthesis and/or breakdown rates. This mechanism of skeletal muscle growth, in our view, is firmly established given that there is no other physiological mechanism currently known through which muscle can gain or lose size independent of protein turnover. On the other hand, the role of skeletal muscle satellite cells in skeletal muscle hypertrophy remains unsettled as highlighted in a previous debate (O’Connor et al. 2007). A recent article in The Journal of Physiology by Wang and McPherron (2012) used well-designed experiments to contribute towards this current conversation that attempts to define the specific role of satellite cells play in skeletal muscle hypertrophy. Specifically, Wang & McPherron investigated the necessity of satellite cells in myostatin-mediated skeletal muscle hypertrophy. These authors induced muscle hypertrophy by blocking myostatin activity through the use of an established myostatin inhibitor while tracking satellite cell proliferation via bromodeoxyuridine (BrdU) incorporation into isolated muscle fibres. The authors modulated dose and timing of the myostatin inhibitor in an attempt to clarify the temporal relationship between satellite cell activation and muscle hypertrophy in response to myostatin inactivation. The impetus for the study was the discrepancy in the findings from previous studies using the myostatin knockout mouse that reported an increase, or no change, in the number of satellite cells. For example, recent studies report that myostatin null mice show satellite cell number is slightly decreased with no difference in satellite cell proliferation (Amthor et al. 2009), and are also resistant to sarcopenia (Siriett et al. 2006). In the current study, Wang and McPherron (2012) reported that injection of low-dose myostatin inhibitor (5 and 10 mg (kg body weight)−1) resulted in 11% myofibre and whole muscle hypertrophy and was essentially absent of any BrdU incorporation (indicating there was no satellite cell proliferation). Although simultaneous staining was not clear, separate Pax7 (satellite cell marker) and BrdU+ staining is indicative of myonuclei that originated as a satellite cell that had proliferated and then fused into the myofibre. Interestingly, the degree of myonuclear addition was quite modest with BrdU-labelled nuclei, accounting for ∼0.4–3.4% of total nuclei when myofibre hypertrophy was 25–30%. These results suggest that if satellite cells are necessary for hypertrophy a small number of satellite cells induce a tremendous regulatory influence on the whole myofibre. Until recently, as reviewed in the article of the Wang and McPherron work, the evidence supporting an obligatory role for satellite cells in muscle hypertrophy is based on indirect and controversial methodologies (O’Connor et al. 2007). For example, an earlier approach used gamma-irradiation to block satellite cell activity that clearly lacked cellular specificity. Moreover, in some of the gamma-irradiation studies young mice were used and the possibility exists of confounding results from incomplete post-natal development (i.e. muscle growth is, expectantly, dependent on satellite cell activation in a mature adult animal). Notable is the recent work of McCarthy et al. (2011) that demonstrated, through a genetic strategy, that satellite cell ablation can be inducible in skeletal muscle in adult mice that are past development (4 months old). Such an approach avoids the influence of satellite cells on maturation and instead specifically focuses on adult skeletal muscle hypertrophy. Also, this approach allowed the research group to assess the role of satellite cells in muscle hypertrophy, the same question Wang and McPherron addressed in their work. Rather than taking advantage of the myostatin pathway, McCarthy et al. (2011), chose a robust hypertrophic model in surgical synergist ablation to stimulate muscle growth after inducing satellite cell ablation. The workers demonstrated that muscle hypertrophy was not affected after eliminating the satellite cell response (McCarthy et al. 2011). Thus, these data also contribute to the body of literature suggesting that muscle hypertrophy induced through surgical mechanical overload, or myostatin inhibition, is not reliant on satellite cell activation. Wang and McPherron (2012) highlight an important concept of ‘myonuclear domain’ that was introduced over 25 years ago (Cheek, 1985). Satellite cell researchers have argued both for, and against, the idea that the cytoplasmic volume/DNA ratio is a tightly regulated process and the driving force for a satellite cell to fuse into the myofibre. However, even now this process is understudied and not well understood. Since myonuclei are believed to be post-mitotic in nature, it is assumed the increase in myonuclei number is necessary to support the stability of myonuclear domain. To date, scientists remain relatively uncertain with regards to the exact nature of how the myofibre, existing myonuclei, and the ‘quiescent’ satellite cells communicate and ultimately signal incorporation and muscle growth. This leads to further questions; although it appears satellite cells are not necessary for muscle hypertrophy, it would be narrow minded to suggest that satellite cells do not contribute towards overall skeletal muscle mass, or in other words a mistaken identity (i.e. no role for satellite cells in skeletal muscle hypertrophy). Certainly, independent of the satellite cell's role in development and regeneration, once muscle mass has increased the role of satellite cells may be necessary to sustain the mass and perhaps also be integral in maintaining muscle function/quality. This idea is merely speculation; however, it is especially intriguing with respect to sarcopenia, as highlighted by the Wang and McPherron study, demonstrating that myostatin null mice are not resistant to age-associated muscle loss or satellite cell loss. Also, the relationship between the acute muscle protein synthetic response (often used as a quantitative predictor of longer-term gains in muscle size) and the acute satellite cell response after anabolic stimuli remains relatively undefined. Are these two muscle ‘hypertrophic’ responses in complete discordance acutely (hours) and overtime (weeks) begin to share an intimately connected relationship that eventually allows for some ‘serious’ muscle size gains? Clearly, more work is necessary in this area to reach a more definitive answer to these questions. What is notable is that myostatin and synergist ablation represent powerful models to study muscle hypertrophy; however, other modalities that influence muscle mass (exercise, ageing, feeding, atrophy, etc.) may be dependent on satellite cells that have yet to be elucidated. The findings from the current study, as well as others, are relevant to groups interested in athletic performance and physical therapy – a greater understanding of the intricacies of muscle size regulation will help in the development of more efficacious and proficient training programs and therapies. We congratulate Wang and McPherron for their well-designed study highlighting myostatin and its role in muscle hypertrophy and satellite cell biology. This research (and others) sparks discussion towards the idea that satellite cell biology may influence specific muscle growth pathways to varying degrees dependent on modality and muscle environment. We would like to thank Dr John J. McCarthy for his helpful edits of this manuscript.
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Myostatin is a potent negative regulator of skeletal muscle mass, but its role in human skeletal muscle hypertrophy and atrophy is sparsely described. Muscle biopsies were obtained from young male subjects before and after 30 and 90 days of resistance training as well as after 3, 10, 30, 60 and 90 days of subsequent detraining. Myostatin mRNA increased significantly with detraining. We observed a 28 kDa myostatin immunoreactive protein, which, however, was also present in myostatin knock out mice skeletal muscle. As a novel finding we consistently detected a 10 kDa band, which may represent a mature myostatin monomer under reducing conditions or a novel, unknown myostatin form. Further, we observed a significant increase in this 10 kDa band after 3 days of detraining preceding the rapid type II fiber atrophy, in which almost half of the acquired fiber area was lost after only 10 days of detraining. Accordingly, an increase in the level of the 10 kDa protein is associated with rapid type II fiber atrophy, suggesting myostatin-mediated specific type II fiber atrophy, which in combination with our mRNA data support a role for myostatin in the negative regulation of adult human skeletal muscle mass.
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Coffee increases skeletal muscle function and hypertrophy by regulating the TGF-β/myostatin – Akt – mTORC1.
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Myostatin (GDF‐8) is the chief chalone in skeletal muscle and negatively controls adult skeletal muscle growth. The role of myostatin during overload‐induced hypertrophy of adult muscle is unclear. We tested the hypothesis that overloaded adult rodent skeletal muscle would reduce expression of myostatin. Overload‐induced hypertrophy was induced by unilateral tenotomy of the gastrocnemius tendon in 11 male adult Sprague‐Dawley rats followed by a 2‐week period of compensatory overload of the plantaris and soleus muscles. Western blot analysis was performed to evaluate changes in active and latent complex myostatin protein expression. Significant hypertrophy was noted in the soleus (494 ± 29 vs 405 ± 15 mg, p<0.05) and plantaris (289 ± 12 vs 179 ± 37 mg, p<0.05) muscles following overload. Overloaded plantaris muscle decreased expression of the active myostatin protein by 28.0 ± 6.6 % (p<0.01) while the myostatin precursor decreased slightly (p=0.04). Overloaded soleus muscle decreased expression of the active myostatin protein by 22.5 ± 5.4% (p<0.01) while myostatin precursor was unchanged. Myostatin latent complex expression decreased in the overloaded soleus by 11.4 ± 4.2% (p = 0.03) but was unchanged in the plantaris. These data support the hypothesis that the myostatin‐signaling pathway in overloaded muscles is generally reduced and contributes to muscle hypertrophy.
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Follistatin (FS) inhibits several members of the TGF-beta superfamily, including myostatin (Mstn), a negative regulator of muscle growth. Mstn inhibition by FS represents a potential therapeutic approach of muscle atrophy. The aim of our study was to investigate the mechanisms of the FS-induced muscle hypertrophy. To test the role of satellite cells in the FS effect, we used irradiation to destroy their proliferative capacity. FS overexpression increased the muscle weight by about 37% in control animals, but the increase reached only 20% in irradiated muscle, supporting the role of cell proliferation in the FS-induced hypertrophy. Surprisingly, the muscle hypertrophy caused by FS reached the same magnitude in Mstn-KO as in WT mice, suggesting that Mstn might not be the only ligand of FS involved in the regulation of muscle mass. To assess the role of activin (Act), another FS ligand, in the FS-induced hypertrophy, we electroporated FSI-I, a FS mutant that does not bind Act with high affinity. Whereas FS electroporation increased muscle weight by 32%, the muscle weight gain induced by FSI-I reached only 14%. Furthermore, in Mstn-KO mice, FSI-I overexpression failed to induce hypertrophy, in contrast to FS. Therefore, these results suggest that Act inhibition may contribute to FS-induced hypertrophy. Finally, the role of Act as a regulator of muscle mass was supported by the observation that ActA overexpression induced muscle weight loss (-15%). In conclusion, our results show that satellite cell proliferation and both Mstn and Act inhibition are involved in the FS-induced muscle hypertrophy.
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uscle wasting and weakness are among the most common inherited and acquired disorders and include the muscular dystrophies, cachexia, and age-related wasting.Since there is no generally accepted treatment to improve muscle bulk and strength, these conditions pose a substantial burden to patients as well as to public health.Consequently, there has been considerable interest in a recently described inhibitor of muscle growth, myostatin, or growth/ differentiation factor 8 (GDF-8), which belongs to the transforming growth factor b superfamily of secreted proteins that control the growth and differentiation of tissues throughout the body.The myostatin gene is expressed almost exclusively in cells of skeletal-muscle lineage throughout embryonic development as well as in adult animals and functions as a negative regulator of muscle growth. 1,2Targeted disruption of the myostatin gene in mice doubles skeletal-muscle mass. 1 Conversely, systemic overexpression of the myostatin gene leads to a wasting syndrome characterized by extensive muscle loss. 3In adult animals, myostatin appears to inhibit the activation of satellite cells, which are stem cells resident in skeletal muscle. 4,5he potential relevance of myostatin to the treatment of disease in humans has been suggested by studies involving mdx mice, which carry a mutation in the dystrophin gene and therefore serve as a genetic model of Duchenne's and Becker's muscular dystrophy. 6For example , mdx mice that lacked myostatin were found not only to be stronger and more muscular than their mdx counterparts with normal myostatin, but also to have reduced fibrosis and fatty remodeling, suggesting improved regeneration of muscle. 7Furthermore, injection of neutralizing monoclonal antibodies directed against myostatin into either wild-type or mdx mice increases muscle mass and specific force, suggesting that myostatin plays an important role in regulating muscle growth in adult animals. 8,91][12][13] The phenotypes of mice and cattle lacking myostatin and the high degree of sequence conservation of the predicted myostatin protein in many mammalian species have raised the possibility that myostatin may help regulate muscle growth in humans.We report the identification of a myostatin mutation in a child with muscle hypertrophy, thereby providing strong evidence that myostatin does play an important role in regulating muscle mass in humans.A healthy woman who was a former professional athlete gave birth to a son after a normal pregnancy.The identity of the child's father was not revealed.The child's birth weight was in the 75th percentile.Stimulus-induced myoclonus developed several m case report
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