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Coordinated patterns of gene expressions for adult muscle build-up in transgenic mice expressing myostatin propeptide.

Zhao B, Li EJ, Wall RJ, Yang J - BMC Genomics (2009)

Bottom Line: Previously, transgenic over-expression of myostatin propeptide in skeletal muscle results in significant muscle growth in early stages of development.The results present a coordinated pattern of gene expressions for reduced energy utilization during muscle build-up in adult stage.Enhanced muscle buildup by myostatin propeptide is sustained by reduced ATP synthesis as a result of a decreased activity of protein degradation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept of Human Nutrition, Food and Animal Sciences, University of Hawaii at Manoa, Honolulu, HI 96822, USA. baoping@hawaii.edu

ABSTRACT

Background: Skeletal muscle growth and maintenance are essential for human health. One of the muscle regulatory genes, namely myostatin, a member of transforming growth factor-beta, plays a dominant role in the genetic control of muscle mass. Myostatin is synthesized as a precursor protein, which generates the N-terminal propeptide and the C-terminal mature myostatin peptide by a post-translational cleavage event. Previously, transgenic over-expression of myostatin propeptide in skeletal muscle results in significant muscle growth in early stages of development. The objectives of present study were to further characterize muscle growth in later stages of life and to identify genes and their expression patterns that are responsible for adult muscle build-up by myostatin propeptide.

Results: Immunohistochemical staining with an antibody to the N-terminus indicates a high level of myostatin propeptide present in the muscles of transgenic mice while there were no apparent differences in myostatin protein distribution in the muscle fibers between the transgenic and wild-type mice. Main individual muscles increased by 76-152% in the transgenic mice over their wild-type littermate mice at 12 months of age. A large number of nuclei were localized in the central and basal lamina of the myofibers in the transgenic mice as the number of nuclei per fiber and 100 microm(2) area was significantly higher in transgenic mice than wild-type mice. By systemic comparisons of global mRNA expression patterns between transgenic mice and wild-type littermates using microarray and qRT-PCR techniques, we have identified distinct gene expression patterns to support adult muscle build-up by myostatin propeptide, which are comprised of enhanced expressions of myogenic regulatory factors and extracelullar matrix components, and differentially down-regulated expressions of genes related to protein degradation and mitochondrial ATP synthesis.

Conclusion: The results present a coordinated pattern of gene expressions for reduced energy utilization during muscle build-up in adult stage. Enhanced muscle buildup by myostatin propeptide is sustained by reduced ATP synthesis as a result of a decreased activity of protein degradation. Myostatin propeptide may have a therapeutic application to the treatment of clinical muscle wasting problems by depressing myostatin activity.

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Urinary creatinine and 3-methylhistidine content. The mean and SEM was based on 8 mice per group. Urine samples were taken from 12-months-old mice. Statistical differences between transgenic and wild-type mice were determined by two-sided Student's t test (*: P < 0.05; **: P < 0.01).
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Figure 6: Urinary creatinine and 3-methylhistidine content. The mean and SEM was based on 8 mice per group. Urine samples were taken from 12-months-old mice. Statistical differences between transgenic and wild-type mice were determined by two-sided Student's t test (*: P < 0.05; **: P < 0.01).

Mentions: To confirm the data of muscle protein degradation, we further analyzed urinary creatinine and 3-methylhistidine in the transgenic and wild-type mice at 12 month of age. 3-methylhistidine is formed by post-translational methylation of histidine in muscle actin and myosin. Skeletal muscle mass is the main source of urinary creatinine, which is highly correlated to the total muscle mass of animals fed a meat-free diet [21]. The results showed a significantly increased level of urinary creatinine and 3-methylhistidine in the transgenic mice compared with the wild-type littermates (Figure 6). The ratio of urinary 3-methylhistidine to creatinine, an index of muscle protein catabolism [17], was significantly lower in transgenic mice than that in wild-type mice (P < 0.01, Figure 6C). These results provide further evidence that skeletal muscles in the transgenic mice had a decreased level of protein degradation, consistent with the data extracted from global gene expression analysis by microarray analysis.


Coordinated patterns of gene expressions for adult muscle build-up in transgenic mice expressing myostatin propeptide.

Zhao B, Li EJ, Wall RJ, Yang J - BMC Genomics (2009)

Urinary creatinine and 3-methylhistidine content. The mean and SEM was based on 8 mice per group. Urine samples were taken from 12-months-old mice. Statistical differences between transgenic and wild-type mice were determined by two-sided Student's t test (*: P < 0.05; **: P < 0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2713998&req=5

Figure 6: Urinary creatinine and 3-methylhistidine content. The mean and SEM was based on 8 mice per group. Urine samples were taken from 12-months-old mice. Statistical differences between transgenic and wild-type mice were determined by two-sided Student's t test (*: P < 0.05; **: P < 0.01).
Mentions: To confirm the data of muscle protein degradation, we further analyzed urinary creatinine and 3-methylhistidine in the transgenic and wild-type mice at 12 month of age. 3-methylhistidine is formed by post-translational methylation of histidine in muscle actin and myosin. Skeletal muscle mass is the main source of urinary creatinine, which is highly correlated to the total muscle mass of animals fed a meat-free diet [21]. The results showed a significantly increased level of urinary creatinine and 3-methylhistidine in the transgenic mice compared with the wild-type littermates (Figure 6). The ratio of urinary 3-methylhistidine to creatinine, an index of muscle protein catabolism [17], was significantly lower in transgenic mice than that in wild-type mice (P < 0.01, Figure 6C). These results provide further evidence that skeletal muscles in the transgenic mice had a decreased level of protein degradation, consistent with the data extracted from global gene expression analysis by microarray analysis.

Bottom Line: Previously, transgenic over-expression of myostatin propeptide in skeletal muscle results in significant muscle growth in early stages of development.The results present a coordinated pattern of gene expressions for reduced energy utilization during muscle build-up in adult stage.Enhanced muscle buildup by myostatin propeptide is sustained by reduced ATP synthesis as a result of a decreased activity of protein degradation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept of Human Nutrition, Food and Animal Sciences, University of Hawaii at Manoa, Honolulu, HI 96822, USA. baoping@hawaii.edu

ABSTRACT

Background: Skeletal muscle growth and maintenance are essential for human health. One of the muscle regulatory genes, namely myostatin, a member of transforming growth factor-beta, plays a dominant role in the genetic control of muscle mass. Myostatin is synthesized as a precursor protein, which generates the N-terminal propeptide and the C-terminal mature myostatin peptide by a post-translational cleavage event. Previously, transgenic over-expression of myostatin propeptide in skeletal muscle results in significant muscle growth in early stages of development. The objectives of present study were to further characterize muscle growth in later stages of life and to identify genes and their expression patterns that are responsible for adult muscle build-up by myostatin propeptide.

Results: Immunohistochemical staining with an antibody to the N-terminus indicates a high level of myostatin propeptide present in the muscles of transgenic mice while there were no apparent differences in myostatin protein distribution in the muscle fibers between the transgenic and wild-type mice. Main individual muscles increased by 76-152% in the transgenic mice over their wild-type littermate mice at 12 months of age. A large number of nuclei were localized in the central and basal lamina of the myofibers in the transgenic mice as the number of nuclei per fiber and 100 microm(2) area was significantly higher in transgenic mice than wild-type mice. By systemic comparisons of global mRNA expression patterns between transgenic mice and wild-type littermates using microarray and qRT-PCR techniques, we have identified distinct gene expression patterns to support adult muscle build-up by myostatin propeptide, which are comprised of enhanced expressions of myogenic regulatory factors and extracelullar matrix components, and differentially down-regulated expressions of genes related to protein degradation and mitochondrial ATP synthesis.

Conclusion: The results present a coordinated pattern of gene expressions for reduced energy utilization during muscle build-up in adult stage. Enhanced muscle buildup by myostatin propeptide is sustained by reduced ATP synthesis as a result of a decreased activity of protein degradation. Myostatin propeptide may have a therapeutic application to the treatment of clinical muscle wasting problems by depressing myostatin activity.

Show MeSH
Related in: MedlinePlus