The comparative genomics and physiology of myostatin

Dilip Kumar Garikipati

doi:10.7273/000005765

Myostatin is well described as a negative regulator of skeletal muscle growth in mammals and myostatin-null animals possess a “double muscle” phenotype. Recent attempts to produce a similar phenotype in fish have failed. Myostatin biology in fishes significantly differs from that in mammals and the presence of multiple myostatin genes suggests possible functional divergence. Two new rainbow trout myostatin genes were identified in addition to the available MSTN-1a and -1b genes. Phylogenetic analyses grouped the new genes into the myostatin-2 clade supporting previous analyses. The genomic structure of all four rainbow trout myostatin genes, rtMSTN-1a, -1b, -2a and - 2b, was conserved with three exons, two relatively short introns and conserved exon/intron boundaries that for the most part were conserved among all vertebrate homologs. Subsequence analysis of the promoter regions identified several putative myogenic elements, although the structure of each promoter was unique and was reflected in the differential gene expression. The rtMSTN-2b gene contained two inframe stop codons suggesting that it is a pseudogene. The embryonic expression of rtMSTN-1 genes was similar, however, rtMSTN-1a was highly expressed compared to rtMSTN-1b gene and rtMSTN-2a was not significantly expressed throughout development. All the myostatin genes were expressed in various tissues of rainbow trout, although the expression level varied with gene and tissue. Alternative splicing was detected with both rtMSTN-2 transcripts and occurred in a manner that limited mature rtMSTN-2a transcripts to the brain and contributed to rtMSTN-2b pseudogenization. The tissue and gene specific processing, differential gene expression and pseudogenization of rtMSTN-2b likely represent compensatory and adaptive response to tetraploidization. The ubiquitous expression of at least two rtMSTN genes in all tissues surveyed suggests that myostatin’s actions may be pleiotropic in fish. Recent studies, however, suggest that myostatin may also influence tissues other than skeletal muscle in mammals as well. Therefore, we determined the effect of myostatin on cardiomyoblasts. Myostatin suppressed both basal and stimulated proliferation of these cells and also inhibited differentiation. These data indicate that myostatin may play a wider role than previously believed as it similarly regulates skeletal and cardiac muscle in mammals. Knowledge from the studies with rainbow trout will help explain the underlying mechanisms of functional divergence while the cardiomyoblast studies may help design novel therapeutics for treating myocardial infarction. Together, these studies highlight the value of a comparative approach to understanding the evolution and physiology of this dynamic gene family.

The comparative genomics and physiology of myostatin

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