MYOSTATIN INHIBITION DIRECTLY INFLUENCES DNA METHYLATION TO BUILD EPIGENETIC LANDSCAPE INDUCING SKELETAL MUSCLE HYPERTROPHY

Abstract

Myostatin(MSTN) is a TGF β signaling ligand and a known inhibitor of skeletal muscle formation in adult s , which inactivation results in hypermuscular phenotype in animals, and has been vigorously researched for its applicability in agriculture and medicine. Some recent studies suggest that MSTN utilizes not only molecular signaling but also epigenetics modif ications to control the gene expression patterns of skeletal muscle. In this study, we developed a mouse line overexpressing MSTN prodomain (MSTN pro), an inhibitor of MSTN at birth to thoroughly study its effects on genomic DNA methylation using RRBS anal ysis contrasted with qPCR based gene expression of selected relevant genes. Surprisingly, DNA methyltransferases and demethylases were dysregulated at both global and local levels during fetal periods before transgene expression, and not after birth. Such dysregulation was hardly coincidental since identified DMRs are highly concentrated into pathways involved in skeletal muscle development. Post natal and post transgene expression skeletal muscle, on the other hand, had the DNA methylome indirectly altered through transcription factors and histone modifications, with minimal evidence of a direct relationship between MSTN and DNA methylation related enzymes. Overall, MSTN inhibition of early neonatal skeletal muscle resulted in the activation of TET3 demethy lase to ensure the smooth activation of Wnt and PI3K/Akt/mTOR pathways, both of which are direct targets inhibited by MSTN signaling. Additionally, the study revealed an unknown process during late fetal development in MSTN pro transgenic individuals which predisposes them to develop the hypermuscular phenotype later in life.