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Abstract
Myostatin, a transforming growth factor-β family member, is a negative regulator of skeletal muscle development and growth. Piedmontese cattle breeds have a missense mutation, which results in a cysteine to tyrosine substitution in the mature myostatin protein (C313Y). This loss-of-function mutation in myostatin results in a double-muscled phenotype in cattle. Myostatin propeptide is an inhibitor of myostatin activity and is considered a potential agent to stimulate muscle growth in livestock. In this study, we generated transgenic mice overexpressing porcine myostatin missense mutant (pmMS), C313Y, and wild-type porcine myostatin propeptide (ppMS), respectively, to examine their effects on muscle growth in mice. Enhanced muscle growth was observed in both pmMS and ppMS transgenic female mice and also in ppMS transgenic male mice. However, there was no enhanced muscle growth observed in pmMS transgenic male mice. To explore why there is such a big difference in muscle growth between pmMS and ppMS transgenic male mice, the expression level of androgen receptor (AR) mutant AR45 was measured by Western blot. Results indicated that AR45 expression significantly increased in pmMS transgenic male mice while it decreased dramatically in ppMS transgenic male mice. Our data demonstrate that both pmMS and ppMS act as myostatin inhibitors in the regulation of muscle growth, but the effect of pmMS in male mice is reversed by an increased AR45 expression. These results provide useful insight and basic theory to future studies on improving pork quality by genetically manipulating myostatin expression or by regulating myostatin activity.
Highlights
Myostatin is well-known as a growth and differentiation factor 8 (GDF-8) that acts as a negative regulator of skeletal muscle growth
Since there is a difference in gene sequence between C57 BL/6 mice and porcine myostatin, we used reverse transcription PCR by designing primers that only amplify exogenous porcine myostatin to identify the genotype of transgenic mice at the RNA level (Figure 1B)
We performed a Western blot with crude extracts from gastrocnemius of a representative porcine myostatin missense mutant (pmMS) male mouse and and a WT male mouse under non-reduced condition and our results show that pro-myostatin and mature myostastin protein bands were detected (Figure S1)
Summary
Myostatin is well-known as a growth and differentiation factor 8 (GDF-8) that acts as a negative regulator of skeletal muscle growth. Myostatin is secreted as a precursor protein which is cleaved by multiple steps of furin-type proteases to generate an N-terminal propeptide and a C-terminal growth factor dimer, the biologically active part [1]. Mature myostatin is liberated from the latent myostatin complex by bone morphogenetic protein 1/tolloid proteases. The myostatin gene is extraordinarily well conserved among different species and the amino acid sequences of the mature and active protein from humans, mice, rats, pigs, and chickens are identical [4]. The skeletal muscle weight of GDF-8 (myostatin) null mice is twice as much as wild-type mice [5]. Enhanced muscle growth was observed in transgenic mice expressing myostatin propeptide [6,7]. Transgenic mice expressing wild-type porcine myostatin propeptide were reported to have enhanced muscle growth [8]
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