Abstract
BackgroundMyostatin, a muscle-specific member of the Transforming Growth Factor beta family, negatively regulates muscle development. Double-muscled (DM) cattle have a loss-of-function mutation in their myostatin gene responsible for the hypermuscular phenotype. Thus, these animals are a good model for understanding the mechanisms underpinning muscular hypertrophy. In order to identify individual genes or networks that may be myostatin targets, we looked for genes that were differentially expressed between DM and normal (NM) animals (n = 3 per group) in the semitendinosus muscle (hypertrophied in DM animals) at 260 days of fetal development (when the biochemical differentiation of muscle is intensive). A heterologous microarray (human and murine oligonucleotide sequences) of around 6,000 genes expressed in muscle was used.ResultsMany genes were found to be differentially expressed according to genetic type (some with a more than 5-fold change), and according to the presence of one or two functional myostatin allele(s). They belonged to various functional categories. The genes down-regulated in DM fetuses were mainly those encoding extracellular matrix proteins, slow contractile proteins and ribosomal proteins. The genes up-regulated in DM fetuses were mainly involved in the regulation of transcription, cell cycle/apoptosis, translation or DNA metabolism. These data highlight features indicating that DM muscle is shifted towards a more glycolytic metabolism, and has an altered extracellular matrix composition (e.g. down-regulation of COL1A1 and COL1A2, and up-regulation of COL4A2) and decreased adipocyte differentiation (down-regulation of C1QTNF3). The altered gene expression in the three major muscle compartments (fibers, connective tissue and intramuscular adipose tissue) is consistent with the well-known characteristics of DM cattle. In addition, novel potential targets of the myostatin gene were identified (MB, PLN, troponins, ZFHX1B).ConclusionThus, the myostatin loss-of-function mutation affected several physiological processes involved in the development and determination of the functional characteristics of muscle tissue.
Highlights
Myostatin, a muscle-specific member of the Transforming Growth Factor beta family, negatively regulates muscle development
Studies during the past decade have shown that the product of the gene myostatin (GDF8) is an inhibitor of muscle development and of the maintenance of muscle mass
In order to identify differences in gene expression, and novel genes or networks that may be myostatin targets liable to be involved in muscle differentiation, we examined the transcriptional profiling of the semitendinosus (ST) muscle of DM fetuses vs Non-Double-Muscled (NM) at 260 days of gestation
Summary
A muscle-specific member of the Transforming Growth Factor beta family, negatively regulates muscle development. Double-muscled (DM) cattle have a loss-offunction mutation in their myostatin gene responsible for the hypermuscular phenotype. These animals are a good model for understanding the mechanisms underpinning muscular hypertrophy. Studies during the past decade have shown that the product of the gene myostatin (GDF8) (a muscle-specific TGFβ family member) is an inhibitor of muscle development and of the maintenance of muscle mass. Several disruptive myostatin mutations have been identified in different breeds [3,4]. These mutations truncate the protein product resulting in functional inactivation. The Q204X mutation (a C to T transition), which results in a premature stop codon in the N-terminal LAP (Latency Associated Peptide) domain, is frequently found in the Charolais breed or in the INRA95 genotype [4]
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