Myostatin regulates fatty acid desaturation and fat deposition through MEF2C/miR222/SCD5 cascade in pigs

Myostatin (MSTN), associated with the “double muscling” phenotype, affects muscle growth and fat deposition in animals, whereas how MSTN affects adipogenesis remains to be discovered. Here we show that MSTN can act through the MEF2C/miR222/SCD5 cascade to regulate fatty acid metabolism. We generated MSTN-knockout (KO) cloned Meishan pigs, which exhibits typical double muscling trait. We then sequenced transcriptome of subcutaneous fat tissues of wild-type (WT) and MSTN-KO pigs, and intersected the differentially expressed mRNAs and miRNAs to predict that stearoyl-CoA desaturase 5 (SCD5) is targeted by miR222. Transcription factor binding prediction showed that myogenic transcription factor 2C (MEF2C) potentially binds to the miR222 promoter. We hypothesized that MSTN-KO upregulates MEF2C and consequently increases the miR222 expression, which in turn targets SCD5 to suppress its translation. Biochemical, molecular and cellular experiments verified the existence of the cascade. This novel molecular pathway sheds light on new targets for genetic improvements in pigs. Ren, Xiao et al. identify a mechanism by which myostatin regulates adipogenesis, using myostatin-knockout pigs. Myostatin deficiency upregulates MEF2C that binds to the promoter of miR222. miR222 in turn downregulates stearoyl-CoA desaturase 5. This study provides potential targets that can be engineered to generate a new pig variety that has high leanness while maintaining its high intramuscular fat content.