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Skeletal muscle gene expression after myostatin knockout in mature mice

ABSTRACT: RNA from 5 mice with postdevelopmental knockout of myostatin and 5 mice with normal myostatin expression was analyzed with comprehensive oligonucleotide microarrays. Myostatin depletion affected the expression of several hundred genes at nominal P < 0.01, but fewer than a hundred effects were statistically significant according to a more stringent criterion (false discovery rate < 5%). Most of the effects were less than 1.5-fold in magnitude. In contrast to previously-reported effects of constitutive myostatin knockout, postdevelopmental knockout did not downregulate expression of genes encoding slow isoforms of contractile proteins or genes encoding proteins involved in energy metabolism. Several collagen genes were expressed at lower levels in the myostatin-deficient muscles, and this led to reduced tissue collagen levels as reflected by hydroxyproline content. Myostatin knockout tended to down-regulate the expression of sets of genes with promoter motifs for Smad3, Smad4, myogenin, NF-κB, serum response factor, and numerous other transcription factors. Main conclusions: in mature muscle, myostatin is a key transcriptional regulator of collagen genes, but not genes encoding contractile proteins or genes encoding proteins involved in energy metabolism.

ORGANISM(S): Mus musculus

PROVIDER: GSE15349 | GEO | 2009/03/24

SECONDARY ACCESSION(S): PRJNA116581

REPOSITORIES: GEO

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Project description:Myostatin is a highly conserved Transforming Growth Factor beta family member which negatively regulates muscle development. Double-muscled (DM) cattle have a loss-of-function mutation in their myostatin gene responsible for a hypermuscular phenotype mainly due to hyperplasia. Thus these animals represent a good model for understanding the mechanisms at the origin of muscular hypertrophy. In order to identify individual genes or networks that may be myostatin targets, we looked for genes differentially expressed between DM and normal (NM) animals (n=3 per group) in the semitendinosus muscle (a hypertrophied muscle in DM animals) at 260 days of fetal development (intensive muscle biochemical differentiation). The experiment was carried out using muscle-dedicated high density oligonucleotide arrays of around 6,000 muscle specific genes. A great number of genes was found to be differentially expressed according to the genetic type (some with a change higher than 5-fold), and according to the zygosity of the myostatin mutation. They belonged to various functional categories. The genes down-regulated in DM fetuses corresponded mainly to genes encoding extracellular matrix proteins, slow contractile proteins and ribosomal proteins. On the other hand, the genes up-regulated in DM fetuses were involved mainly in the regulation of transcription, cell cycle/apoptosis, translation, or DNA metabolism. These data singled out features indicating that DM muscle had shifted towards a more glycolytic metabolism, had an altered extracellular matrix composition (e.g. down-regulation of COL1A1, COL1A2, and up-regulation of collagen IV) and a decreased adipocyte differentiation (down-regulation of C1QTNF3). Altered gene expression in the three major muscle compartments (e.g. fibers, connective tissue and intramuscular adipose tissue) is in agreement with the well known characteristics of DM cattle. In addition, novel potential targets of the myostatin gene were identifed. Thus, the myostatin loss-of-function mutation affected several physiological processes involved in the development and the determinism of the functional characteristics of the muscle tissue. Transcriptomic profiling of Semitendinosus (ST) muscle of three double-muscled fetuses were analyzed relative to three conventional fetuses. Each individual sample was compared to a reference pool. Four chips were hybridized per sample comparison.

Project description:Myostatin is a highly conserved Transforming Growth Factor beta family member which negatively regulates muscle development. Double-muscled (DM) cattle have a loss-of-function mutation in their myostatin gene responsible for a hypermuscular phenotype mainly due to hyperplasia. Thus these animals represent a good model for understanding the mechanisms at the origin of muscular hypertrophy. In order to identify individual genes or networks that may be myostatin targets, we looked for genes differentially expressed between DM and normal (NM) animals (n=3 per group) in the semitendinosus muscle (a hypertrophied muscle in DM animals) at 260 days of fetal development (intensive muscle biochemical differentiation). The experiment was carried out using muscle-dedicated high density oligonucleotide arrays of around 6,000 muscle specific genes. A great number of genes was found to be differentially expressed according to the genetic type (some with a change higher than 5-fold), and according to the zygosity of the myostatin mutation. They belonged to various functional categories. The genes down-regulated in DM fetuses corresponded mainly to genes encoding extracellular matrix proteins, slow contractile proteins and ribosomal proteins. On the other hand, the genes up-regulated in DM fetuses were involved mainly in the regulation of transcription, cell cycle/apoptosis, translation, or DNA metabolism. These data singled out features indicating that DM muscle had shifted towards a more glycolytic metabolism, had an altered extracellular matrix composition (e.g. down-regulation of COL1A1, COL1A2, and up-regulation of collagen IV) and a decreased adipocyte differentiation (down-regulation of C1QTNF3). Altered gene expression in the three major muscle compartments (e.g. fibers, connective tissue and intramuscular adipose tissue) is in agreement with the well known characteristics of DM cattle. In addition, novel potential targets of the myostatin gene were identifed. Thus, the myostatin loss-of-function mutation affected several physiological processes involved in the development and the determinism of the functional characteristics of the muscle tissue. Keywords: Double-muscled, myostatin loss-of-function, bovine fetuses

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Skeletal muscle gene expression after myostatin knockout in mature mice

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