Submitted to: Genome Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 18, 1997
Publication Date: N/A
Interpretive Summary: Recent studies of muscle development in mice have uncovered a gene that has major effects on the number of muscle fibers that develop prenatally. In its normal form the gene, called myostatin, acts as a negative regulator that tells the muscle precursor cells when to stop dividing and commence differentiation into fibers. Researchers at Johns Hopkins University produced mice with mutations in this gene that prevented its normal function. These mice had greatly enlarged muscles containing much higher number of fibers than normal, a phenotype similar to that seen in double- muscled cattle breeds such as Belgian Blue and Piedmontese. In several previous papers, we had mapped the gene causing double-muscling in cattle and shown that myostatin maps to the same location, which made it an excellent candidate for the gene causing muscle hypertrophy in these breeds. To test myostatin as a candidate, we looked to see if there is any difference in the expression of the mRNA in double muscled cattle, or any defect in the protein. In this paper we show that the level and timing of mRNA expression is indistinguishable between normal and heavy muscled animals. However, when we determined the sequence of the gene we discovered that both Belgian Blue and Piedmontese cattle have mutations in myostatin that are likely to inactivate the protein. We conclude that mutations in myostatin cause the double-muscle phenotype in cattle, a finding that may open the way to developing methods for manipulating muscle mass, fat deposition, and amount of connective tissue in meat animals.
A visible distinct muscular hypertrophy (mh) commonly known as "double muscling" occurs with high frequency in the Belgian Blue cattle breed. The autosomal recessive mh locus causing double muscling condition in these cattle maps to bovine chromosome 2 within the same interval as myostatin, a member of the TGF-Beta superfamily of genes. Since targeted disruption of myostatin in mice results in a muscular phenotype very similar to that see in double muscled cattle, we have evaluated myostatin as a candidate gene for double muscling condition by cloning the bovine myostatin cDNA and examining the expression pattern and sequence of the gene in normal double muscled cattle. The analysis demonstrates that the levels and timing of expression do not appear to differ between the double muscled and normal animals, as both classes show expression initiating during fetal development and being maintained in adult muscle. Moreover, sequence analysis reveals an 11 bp deletion in the coding region of myostatin in Belgian Blue animals that is not detected in cDNA of any normal animals examined. This deletion results in a frame shift mutation that removes the portion of the myostatin protein that is most highly conserved among TGF- Beta family members, and which was the portion targeted for disruption in the mouse study. It therefore appears likely that the mh allele is a deletion mutation within the myostatin gene and the myostatin is a negative regulator of muscle growth in cattle as well as mice.