Deep intronic mutation and pseudo exon activation as a novel muscular hypertrophy modifier in cattle.

Diego Fraidenraich,Claire Bouyer,Lionel Forestier,Ahmad Oulmouden,Gilles Renand

doi:10.1371/journal.pone.0097399

Diego Fraidenraich, Claire Bouyer + Show 3 more

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https://doi.org/10.1371/journal.pone.0097399

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Abstract

Myostatin is essential for proper regulation of myogenesis, and inactivation of Myostatin results in muscle hypertrophy. Here, we identified an unexpected mutation in the myostatin gene which is almost fixed in Blonde d'Aquitaine cattle. In skeletal muscle, the mutant allele was highly expressed leading to an abnormal transcript consisting of a 41-bp inclusion and premature termination codons and to residual levels of a correctly spliced transcript. This expression pattern, caused by a leaky intronic mutation with regard to spliceosome activity and its apparent stability with regard to surveillance mechanisms, could contribute to the moderate muscle hypertrophy in this cattle breed. This finding is of importance for genetic counseling for meat quantity and quality in livestock production and possibly to manipulate myostatin pre-mRNA in human muscle diseases.

Highlights

Myostatin, a member of the transforming growth factor beta (TGF-b) superfamily, functions as a negative regulator of skeletal muscle development and growth
French Blonde d’Aquitaine breed (BAB) is renowned for producing high-yielding beef carcasses and displays a less hypertrophic phenotype (Fig. 1) with certain variations in muscle conformation commonly observed between animals
The amplification products (Fig. 2) encompassed the three coding exons which were 35-bp upstream and 420-bp downstream of the open reading frame respectively. These results suggested that BAB animals produce correctly spliced myostatin

Summary

Introduction

A member of the transforming growth factor beta (TGF-b) superfamily, functions as a negative regulator of skeletal muscle development and growth. Myostatin is expressed almost exclusively in cells of the skeletal muscle lineage, from the embryonic myotome to striated muscle in adults [1]. Like other TGF-b superfamily members, Myostatin is synthesized in a precursor form which dimerizes via disulfide bonds and undergoes three proteolytic cleavages. Removal of the signal peptide sequence is followed by cleavage at a tetrabasic processing site, resulting in a NH2terminal propeptide and a COOH-terminal peptide. Following this proteolytic processing, the propeptide and disulfide-linked Cterminal dimer remain noncovalently bound in a latent complex

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