Theaflavin Promotes Mitochondrial Abundance and Glucose Absorption in Myotubes by Activating the CaMKK2-AMPK Signal Axis via Calcium-Ion Influx

Abstract

Drinking tea has been proven to have a positive biological effect in regulating human glucose and lipid metabolism and preventing type 2 diabetes (T2D). Skeletal muscle (SkM) is responsible for 70% of the sugar metabolism in the human body, and its dysfunction is an important factor leading to the development of obesity, T2D, and muscle diseases. As one of the four known theaflavins (TFs) in black tea, the biological role of theaflavin (TF1) in regulating SkM metabolism has not been reported. In this study, mature myotubes induced by C2C12 cells in vitro were used as models. The results showed that TF1 (20 μM) promoted mitochondrial abundance and glucose absorption in myotubes by activating the CaMKK2-AMPK signaling axis via Ca2+ influx. Moreover, it promoted the expression of slow muscle fiber marker genes (Myh7, Myl2, Tnnt1, and Tnnc1) and PGC-1α/SIRT1, as well as enhanced the oxidative phosphorylation capacity of myotubes. In conclusion, this study preliminarily clarified the potential role of TF1 in regulating SkM glucose absorption as well as promoting SkM mitochondrial biosynthesis and slow muscle fiber formation. It has potential research and application values for the prevention/alleviation of SkM-related T2D and Ca2+-related skeletal muscle diseases through diet.

Role and Mechanism of Theaflavins in Regulating Skeletal Muscle Inflammation

“…Related studies have reported that theaflavins have various regulatory functions in skeletal muscle, including the regulation of muscle fatigue, inhibition of muscle atrophy, and promotion of muscle metabolic function . In our previous study, we also found that theaflavins significantly promoted the differentiation of myogenic cells into myotubes and had potential regulatory effects on the metabolic function of myotubes. , In our previous study, we also found that theaflavins can significantly promote the differentiation of myogenic cells into myotubes and have a potential effect on the metabolic function of myotubes.…”

“…A total of 339 differentially expressed genes were obtained by screening, among which 229 genes were significantly downregulated. Transcriptome quality control and data screening were performed according to published papers. , The results showed that KEGG_pathway_term_level_2 was significantly enriched in focal adhesion, the Janus kinase-signal transducer and activator of transcription (Jak-STAT) signaling pathway, the nuclear factor kappa-B (NF-κB) signaling pathway, and TNF and the Toll-like receptor (TLR) signaling pathway in myotubes. The receptor signaling pathways are shown in Figure A.…”

“…AFM imaging of at least five fixed cells was performed for five different fields of view of each sample group. For specific parameter settings and operations, please refer to our previously published papers. , …”

DNA methylation and proteomics integration uncover dose-dependent group and individual responses to exercise in human skeletal muscle

“…The integration analysis highlighted proteins both positively and negatively associated with specific CpGs, worthy following up in future replication/mechanistic studies. Interestingly of the 261 proteins highlighted in the results, we found proteins positively correlated with CpGs located in genes involved in fatty acid metabolism such as COMMD9, (involved in LDL regulation) [88]; hypertension (ARHGAP42) [89]; weight loss and muscle development (APOBEC1) [90]; obesity (PTPRT and PTPRN2) [91][92][93][94], and muscle myogenesis and hyperthrophy (DACT1, DIO2, RPTOR, and PLEKHM3) [95][96][97][98][99] These proteins were also negatively correlated with CpGs located in genes such as KCNMA1, NOTCH1, and CAMKK2 which are involved in skeletal muscle regeneration, proliferation and differentiation [100][101][102][103][104][105], DHRS3, DGKG, LPIN1, WNT5A which have been associated with obesity, metabolic syndrome and lipid regulation [106][107][108], LRRC2 which is a mediator of mitochondrial and cardiac function [109], and PDE4A which has been associated with diabetes [110; 111]. Based on results of this integration, we suggest that future work studying the relationship between such genes/proteins should be prioritized as this may reveal important mechanisms associated with exercise response across multiple OMIC layers.…”

Beneficial Effects of Theaflavins on Metabolic Syndrome: From Molecular Evidence to Gut Microbiome

“…The mechanism of SGLT1 for transporting glucose involves the cotransport of Na+, and depolarizes the plasma membrane as a way to open the Ca 2+ channels. TFs activated the CaMKK2-AMPK signaling pathway via Ca 2+ influx and upregulated the expression of PGC-1α and SIRT1 in the C2C12 cell line, thereby promoting myotubular mitochondrial abundance and glucose uptake [ 49 ]. A TF mixture (25 mg/kg/day) improved impaired glucose tolerance and significantly lower blood glucose levels in prediabetic SDT rats, and increased insulin expression via the inhibition of gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) degradation [ 52 ].…”