Garcinol Promotes the Formation of Slow-Twitch Muscle Fibers by Inhibiting p300-Dependent Acetylation of PGC-1α.

The conversion of skeletal muscle fiber from fast-twitch to slow-twitch is crucial for sustained contractile and stretchable events, energy homeostasis, and anti-fatigue ability. The purpose of our study was to explore the mechanism and effects of garcinol on the regulation of skeletal muscle fiber type transformation. Forty 21-day-old male C57/BL6J mice (n = 10/diet) were fed a control diet or a control diet plus garcinol at 100 mg/kg (Low Gar), 300 mg/kg (Mid Gar), or 500 mg/kg (High Gar) for 12 weeks. The tibialis anterior (TA) and soleus muscles were collected for protein and immunoprecipitation analyses. Dietary garcinol significantly downregulated (p < 0.05) fast myosin heavy chain (MyHC) expression and upregulated (p < 0.05) slow MyHC expression in the TA and soleus muscles. Garcinol significantly increased (p < 0.05) the activity of peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) and markedly decreased (p < 0.05) the acetylation of PGC-1α. In vitro and in vivo experiments showed that garcinol decreased (p < 0.05) lactate dehydrogenase activity and increased (p < 0.05) the activities of malate dehydrogenase and succinic dehydrogenase. In addition, the results of C2C12 myotubes showed that garcinol treatment increased (p < 0.05) the transformation of glycolytic muscle fiber to oxidative muscle fiber by 45.9%. Garcinol treatment and p300 interference reduced (p < 0.05) the expression of fast MyHC but increased (p < 0.05) the expression of slow MyHC in vitro. Moreover, the acetylation of PGC-1α was significantly decreased (p < 0.05). Garcinol promotes the transformation of skeletal muscle fibers from the fast-glycolytic type to the slow-oxidative type through the p300/PGC-1α signaling pathway in C2C12 myotubes.

Targeting gut microbiota-derived butyrate improves hepatic gluconeogenesis through the cAMP-PKA-GCN5 pathway in late pregnant sows.

Short chain fatty acids (SCFAs) produced by gut microbiota affected hepatic glucose metabolism via the gut-liver axis. The present study aimed to investigate the effects of butyrate produced by gut microbiota on hepatic gluconeogenesis in late-pregnancy sows. A total of 240 primiparous sows in late pregnancy were tested for blood glucose using a glucose meter before feeding and grouped according to their blood glucose level as follows: 0-3.0 mmol L-1 (low blood glucose group, LG group) and 3.1-5.0 mmol L-1 (normal blood glucose group, NG group). Colonic SCFAs and microbiota, SCFAs in the portal vein and liver, and acetylation and phosphorylation levels in the liver samples were analyzed. Hepatocytes from pregnant sows were examined for the effect of butyrate on hepatic glucose gluconeogenesis. In vivo experiments showed that the reproductive performance, serum glucose metabolism index, colonic butyrate and butyrate-producing bacteria decreased in the LG group compared with the NG group. Correlation analysis found a positive correlation among colonic butyrate, butyrate-producing bacteria and the serum glucose metabolism index. Moreover, the hepatic cAMP concentration, PKA activity, GCN5 phosphorylation, and the expression of G6P and PEPCK were decreased and PGC1-α acetylation was increased in the LG group compared with the NG group. In vitro, sodium butyrate significantly stimulated the cAMP concentration, PKA activity, GCN5 phosphorylation, and the expression of G6P and PEPCK and inhibited PGC-1α acetylation in the LG group of hepatocytes from late-pregnancy sows. Interestingly, another in vivo experiment showed that dietary 1-kestose, a natural regulator of gut bacteria, significantly increased butyrate and butyrate-producing bacteria, and improved the reproductive performance and serum glucose metabolism index in late-pregnancy sows. Taken together, we found that targeting gut microbiota-derived butyrate could improve hepatic gluconeogenesis through the cAMP-PKA-GCN5 pathway in late-pregnancy sows.