Upregulation of skeletal muscle PGC-1α through the elevation of cyclic AMP levels by Cyanidin-3-glucoside enhances exercise performance

Abstract

Regular exercise and physical training enhance physiological capacity and improve metabolic diseases. Skeletal muscles require peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) in the process of their adaptation to exercise owing to PGC-1α’s ability to regulate mitochondrial biogenesis, angiogenesis, and oxidative metabolism. Cyanidin-3-glucoside (Cy3G) is a natural polyphenol and a nutraceutical factor, which has several beneficial effects on human health. Here, the effect of Cy3G on exercise performance and the underlying mechanisms involved were investigated. ICR mice were given Cy3G (1 mg/kg, orally) everyday and made to perform weight-loaded swimming exercise for 15 days. The endurance of mice orally administered with Cy3G was improved, enabling them to swim longer (time) and while the levels of exercise-induced lactate and fatigue markers (urea nitrogen, creatinine and total ketone bodies) were reduced. Additionally, the expression of lactate metabolism-related genes (lactate dehydrogenase B and monocarboxylate transporter 1) in gastrocnemius and biceps femoris muscles was increased in response to Cy3G-induced PGC-1α upregulation. In vitro, using C2C12 myotubes, Cy3G-induced elevation of intracellular cyclic AMP levels increased PGC-1α expression via the Ca2+/calmodulin-dependent protein kinase kinase pathway. This study demonstrates that Cy3G enhances exercise performance by activating lactate metabolism through skeletal muscle PGC-1α upregulation.

L-Lactate Promotes Adult Hippocampal Neurogenesis

“…In addition to its peripheral effects, exogenously administered L -lactate was previously shown to effectively cross the blood–brain barrier (BBB), where it can exert central effects (Mächler et al, 2016; Carrard et al, 2018). Examining blood levels of lactate following L -lactate injection exhibited accumulations of lactate that resemble high-intensity physical exercise (Okamoto et al, 2015; Matsui et al, 2017; Matsukawa et al, 2017; So et al, 2017). High-intensity physical exercise is associated with lactate accumulation, hence an imbalance between lactate production and its removal (Ferreira et al, 2007).…”

Acetic acid stimulates G-protein-coupled receptor GPR43 and induces intracellular calcium influx in L6 myotube cells

“…In skeletal muscles, a rise in the intracellular calcium influx resulting from motor activation plays key role in contractile activity-dependent expression as well as fiber type-specific gene expression [30]. A number of Ca 2+ sensitive target genes have been identified in the skeletal muscles [30,39,40]. The key signaling pathway downstream to the elevation in intracellular calcium that translates this signal into a transcriptional response includes the Ca 2+ / CaM-dependent phosphatase calcineurin pathway [26,30].…”

Cyanidin-3-glucoside enhances mitochondrial function and biogenesis in a human hepatocyte cell line

“…Among anthocyanin compounds, Cy3g, a phenol pigment that belongs to the flavonoid family, has been shown to have beneficial effects in several in vitro and in vivo clinical trials (Watson et al 2013 ). Cy3g enhances skeletal muscle mitochondrial biogenesis by upregulating PGC-1α levels (Matsukawa et al 2017 ). PGC-1α is reportedly an essential factor for upregulating hepatic metabolism and is key for overall liver metabolism (Leone et al 2005 ; Finck and Kelly 2006 ).…”

“…In addition, treating different rodents models with Cy3g resulted in hepatocyte protection and prevented obesity and insulin resistance (Jiang et al 2014 , Wei et al 2011 ). Our previous reports indicate that Cy3g benefits skeletal muscle aerobic capacity and enhances adipose tissue metabolism (Matsukawa et al 2015 , 2017 ).…”