Fibroblast growth factor 21 (FGF21) plays an important role in the treatment of disease associated with muscle insulin resistance which is characterized by various factors, such as intramuscular triglyceride (IMT) content. Studies have also shown that FGF21 inhibits triglyceride synthesis in vivo. However, the precise mechanism whereby FGF21 regulates triglyceride metabolism in intramuscular fat (IMF), which may influence the muscle insulin sensitivity, is not clearly understood. In order to understand the role of FGF21 in IMF deposition, we performed FGF21 overexpression in IMF cells by stable transfection. Our results showed that FGF21 inhibited the key adipogenesis gene mRNA expression of peroxisome proliferator-activated receptor gamma (PPARG), CCAAT/enhancer-binding protein (CEBP) family by reducing lysine-specific demethylase 1 (LSD1) expression which led to significant decline in lipid accumulation, and the result was confirmed by Western blot. Moreover, triggered by FGF21, parts of the adipokines—fatty acid-binding protein 4 (FABP4), glucose transporter 4 (GLUT4), adiponectin (ADIPOQ), and perilipin (PLIN1)—were also down-regulated. Furthermore, FGF21 gene expression was suppressed by transcription factor CEBP beta (CEBPB) which contributed strongly to triglyceride synthesis. Taken together, our study is the first to experimentally demonstrate FGF21 emerging as an efficient blockade of adipogenesis in IMF, thus also providing a new understanding of the mechanism whereby FGF21 improves insulin sensitivity.

The alteration in skeletal muscle fiber is a critical factor affecting livestock meat quality traits and human metabolic diseases. Long non-coding RNAs (lncRNAs) are a diverse class of non-coding RNAs with a length of more than 200 nucleotides. However, the mechanisms underlying the regulation of lncRNAs in skeletal muscle fibers remain elusive. To understand the genetic basis of lncRNA-regulated skeletal muscle fiber development, we performed a transcriptome analysis to identify the key lncRNAs affecting skeletal muscle fiber and meat quality traits on a pig model. We generated the lncRNA expression profiles of fast-twitch Biceps femoris (Bf) and slow-twitch Soleus (Sol) muscles and identified the differentially expressed (DE) lncRNAs using RNA-seq and performed bioinformatics analyses. This allowed us to identify 4581 lncRNA genes among six RNA libraries and 92 DE lncRNAs between Bf and Sol which are the key candidates for the conversion of skeletal muscle fiber types. Moreover, we detected the expression patterns of lncRNA MSTRG.42019 in different tissues and skeletal muscles of various development stages. In addition, we performed a correlation analyses between the expression of DE lncRNA MSTRG.42019 and meat quality traits. Notably, we found that DE lncRNA MSTRG.42019 was highly expressed in skeletal muscle and its expression was significantly higher in Sol than in Bf, with a positive correlation with the expression of Myosin heavy chain 7 (MYH7) (r = 0.6597, p = 0.0016) and a negative correlation with meat quality traits glycolytic potential (r = −0.5447, p = 0.0130), as well as drip loss (r = −0.5085, p = 0.0221). Moreover, we constructed the lncRNA MSTRG.42019–mRNAs regulatory network for a better understanding of a possible mechanism regulating skeletal muscle fiber formation. Our data provide the groundwork for studying the lncRNA regulatory mechanisms of skeletal muscle fiber conversion, and given the importance of skeletal muscle fiber types in muscle-related diseases, our data may provide insight into the treatment of muscular diseases in humans.

Emerging studies have indicated that long non-coding RNAs (lncRNAs) play important roles in skeletal muscle growth and development. Nevertheless, it remains challenging to understand the function and regulatory mechanisms of these lncRNAs in muscle biology and associated diseases. Here, we identify a novel lncRNA, Mir22hg, that is significantly upregulated during myoblast differentiation and is highly expressed in skeletal muscle. We validated that Mir22hg promotes myoblast differentiation in vitro. Mechanistically, Mir22hg gives rise to mature microRNA (miR)-22-3p, which inhibits its target gene, histone deacetylase 4 (HDAC4), thereby increasing the downstream myocyte enhancer factor 2C (MEF2C) and ultimately promoting myoblast differentiation. Furthermore, in vivo, we documented that Mir22hg knockdown delays repair and regeneration following skeletal muscle injury and further causes a significant decrease in weight following repair of an injured tibialis anterior muscle. Additionally, Mir22hg gives rise to miR-22-3p to restrict HDAC4 expression, thereby promoting the differentiation and regeneration of skeletal muscle. Given the conservation of Mir22hg between mice and humans, Mir22hg might constitute a promising new therapeutic target for skeletal muscle injury, skeletal muscle atrophy, as well as other skeletal muscle diseases.

Skeletal muscle is a major component of body mass and plays a central role in the control of whole‐body metabolism in humans and animals. Therefore, elucidation of the underlying mechanisms of skeletal growth and development are expected to lead to the discovery of novel genes and pathways related to muscle disease. miR‐206, a skeletal muscle‐specific microRNA, plays a crucial role in myogenesis; however, miR‐206 is known to function in myogenic differentiation, whether or not it affects muscle cells' proliferation, and the underlying mechanisms are unknown. In this study, we investigated the effect of miR‐206 on muscle cell proliferation and differentiation, as well as its effect on myofiber type conversion using mouse C2C12 myoblasts. The results showed that overexpression of miR‐206 inhibited cell proliferation and promoted muscle cell differentiation, but it did not affect myofiber type conversion. Intriguingly, we found that overexpression of miR‐206 suppressed muscle cell proliferation and induced cell cycle arrest in G ₀ /G ₁ phase by inhibiting the glucose‐6‐phosphate dehydrogenase ( G6PD ) gene. Taken together, we demonstrated that the miR‐206‐G6PD pathway suppresses muscle cell proliferation, and these findings may facilitate the treatment of muscle diseases.—Jiang, A., Dong, C., Li, B., Zhang, Z., Chen, Y., Ning, C., Wu, W., Liu, H. MicroRNA‐206 regulates cell proliferation by targeting G6PD in skeletal muscle. FASEB J. 33, 14083‐14094 (2019). www.fasebj.org

Bone morphogenetic protein 7 (BMP7) and BMP15, which encode members of the BMP family, have been identified by whole-genome resequencing as breeding-related genes that overlap with a known quantitative trait locus for reproductive traits. In this study, we investigated the effects of variants at the BMP7 and BMP15 gene loci on sow reproductive traits. We isolated 669 and 1213 bp sequences of the 3’-untranslated region (3’-UTR) of the porcine BMP7 and BMP15 genes, respectively, and detected several RNA regulatory elements, such as miRNA response elements and AU-rich elements. Pooled DNA sequencing identified two novel point mutations (viz., BMP7 c.1569A>G and BMP15 c.2366G>A) in the 3’-UTR. Association analysis showed that the c.1569A>G polymorphism was associated with the litter weight trait in a Large White pig population. Furthermore, analysis of the combined genetic effects revealed that AA/GA and AG/GG were the favorable combined genotypes for the total number of piglets born (TNB) and the total number of piglets born alive (NBA), whereas. Together, our findings confirm that BMP7 and BMP15 are candidate genes for porcine reproductive performance.