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

Abstract

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.

Signaling pathways regulated by natural active ingredients in the fight against exercise fatigue-a review

“…AMPK also inhibits the glucose xenobiotic and lipid and glycogen synthesis pathways to reduce energy expenditure, thus maintaining the balance of intracellular energy metabolism. Peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1α), known as the “molecular switch” for various metabolic pathways, has been shown to play an important role in slow myofibrillogenesis, regulation of glucolipid metabolism, mitochondrial production, electron transport chain, and oxygen radical elimination ( Han et al, 2023 ; Liang et al, 2023 ; Yao et al, 2023 ). In addition, in skeletal muscle, AMPK regulates the activity of PGC-1α in the activated state, prompting the conversion of muscle fibers to type I and type IIa in muscle.…”

“…Type I and type IIa muscle fibers mainly perform aerobic metabolic reactions, whereas type IId/x and type IIb muscle fibers mainly use glycolysis for energy supply. Increasing the ratio of type I and type IIa muscle fibers is conducive to improving exercise endurance ( Yao et al, 2023 ). Silent message modifier 1 (SIRT1), which can activate the expression of the PGC-1α gene and increase the transcriptional activity of PGC-1α (thus enhancing mitochondrial biogenesis), is closely related to physiological processes, namely oxidative stress, fatty acid oxidation, and glucose synthesis ( Balcerczyk and Pirola, 2010 ).…”