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

Abstract

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.

Myostatin increases the expression of matrix metalloproteinase genes to promote preadipocytes differentiation in pigs

“…CRISPR/Cas9-mediated HR was exploited to KO allele of MSTN in pig in our previous works [ 4 , 13 ]. We generated cloned MSTN-KO Meishan pigs followed by RNA-sequencing of backfat tissues to profile transcriptomes of MSTN-KO and WT pigs ( Figure 1a ).…”

Myostatin Mutation Promotes Glycolysis by Increasing Phosphorylation of Phosphofructokinase via Activation of PDE5A-cGMP-PKG in Cattle Heart

“…Myostatin may also affect metabolism of adipose tissue by inhibiting differentiation of pre-adipocytes, and thus, both lipid accumulation and myostatin deficiency may promote browning of adipocytes (Li et al, 2011;Braga et al, 2013;Zhu et al, 2015). Ren et al (2020) identified a novel MSTN signal that regulates fat deposition by affecting fatty acid desaturation in MSTN-Knockout pigs via MEF2C/miR222/SCD5 (Ren et al, 2020).…”

Genes Related to Fat Metabolism in Pigs and Intramuscular Fat Content of Pork: A Focus on Nutrigenetics and Nutrigenomics

“…SCD gene: Stearoyl-coenzyme A desaturase gene ( SCD ) is a functional gene that encodes an important enzyme stearoyl-CoA desaturase necessary for the conversion of saturated fatty acids (SFAs) into monounsaturated fatty acids (MUFAs) [ 92 ]. The SCD gene has been associated with the fatty acid composition of porcine longissimus dorsi muscle [ 79 ], and acts as an important regulator of the genetic mechanism of lipid deposition and fatty acid synthesis in pigs [ 77 , 82 , 92 ]. Additionally, it is involved in the PPAR signalling pathway and is important for meat quality traits in pigs [ 72 ].…”

“…It is responsible for double muscling in cattle and Belgian domestic pig breeds, as well as in MSTN -knockout pigs [ 97 ]. Although naturally occurring MSTN mutation is yet to be established in pigs [ 98 ], it is reported to be associated with reduced fat metabolism [ 79 ], and significantly lower IMF content in MSTN mutant mouse lines [ 99 , 100 ]. Inducing MSTN mutation in pigs could result in an increase in longissimus dorsi muscle area, better lean meat yield, reduced backfat and carcass fat content in pigs [ 100 ].…”

“…A study [ 101 ] shows that MSTN knockout using CRISPR/Cas9-mediated genome editing with subsequent somatic cell nuclear transfer offers a promising possibility for genetic improvement of economically important traits in pigs. Ren et al [ 79 ] demonstrated the active potential of MSTN in inhibiting the growth of muscles (double muscling) and acts via myogenic transcription factor 2C ( MEF2C ) which binds to the miR-222 promoter and suppress the translation of SCD5 to affect fat deposition [ 79 ].…”