Myostatin and inhibition by its propeptide in pregnancy and old ages

Abstract

This project was designed to determine myostatin gene expression level in placenta tissue throughout different gestational stages, and its effect on fetal and placental growth, also effects of myostatin inhibition by its propeptide on muscle mass and fat accumulation in old ages. Three groups of mice were used, first group was wild type mice considered as control group, second group was heterozygous (MSTNTG/+) transgenic mice, third group was homozygous (MSTNTG/TG) transgenic mice. Placenta tissue samples and fetuses were collected and weighed at day 10 and 16 of the gestation. Total RNA was extracted from placenta samples for measuring gene expressions The results showed that transgenic pregnant groups showed significant (P<0.05) higher live weight in comparison to their wild type littermates because of carrying significant larger transgenic fetuses and placenta in their uterus, placenta myostatin mRNA showed (21.22±7.31) fold increase in heterozygous and (7.85±1.15) fold increase in homozygous pregnant groups at day 10 of gestation relatively compared to wild type group, while in day 16 the increased level was (12.28±4.97) and (4.98±0.52) fold in heterozygous and homozygous respectively. A positive correlation was found between myostatin expression level and gestational age in wild type group, while in both transgenic groups this correlation was negative. To investigate effects of myostatin suppression by its propeptide on muscle mass and fat accumulation in old ages; we used four different ages of transgenic and wild type male mice: 1month (growing), 6 month (adult), 12 month (middle age), and 18 month (aged mice), whole body, individual muscles, carcass, white and brown adipose tissue weights were taken, total RNA were extracted from muscle tissues for later gene expression measurement. The results showed that the transgenic animals have more muscle mass and significantly (P<0.05) reduced fat accumulation by 80% compared to wild type littermates at old ages. The qRT-PCR results for gene expression showed myostatin mRNA level increased in transgenic mice and its level fluctuating between high and low during different time points of age. Each of MyoD and Myf5 mRNA level showed higher fold change in transgenic mice in early age of our experiment relatively compared to wild-type mice, while their levels reduced gradually with advancing in age. Pax7 gene showed higher expression in transgenic mice compared to wild-type groups at different ages; its level reached the highest expression in 18 months of age in transgenic mice. The overall results of this study provide support for the role of myostatin in fetal and placental growth, also its role in skeletal muscle maintenance in old animals, and the prospect of targeting myostatin to prevent or reverse progressive muscle wasting that occurs in aging and certain degenerated diseases. Based on the above results myostatin inhibition can enhance and continue skeletal muscle growth in advanced age without accumulation or increase adipose tissue, this dramatic effect of myostatin on muscle mass in old ages is probably due to the ability of myostatin to negatively regulate skeletal muscle through myogenic regulatory factors and Pax7 gene.