Hypoxia inducible factor 1 links fast-patterned muscle activity and fast muscle phenotype in rats.

Exercise influences muscle phenotype by the specific pattern of action potentials delivered to the muscle, triggering intracellular signalling pathways. PO2 can be reduced by an order of magnitude in working muscle. In humans, carriers of a hyperactive polymorphism of the transcription factor hypoxia inducible factor 1α (HIF-1α) have 50% more fast fibres, and this polymorphism is prevalent among strength athletes. We have investigated the putative role of HIF-1α in mediating activity changes in muscle.When rat muscles were stimulated with short high frequency bursts of action potentials known to induce a fast muscle phenotype, HIF-1α increased by about 80%. In contrast, a pattern consisting of long low frequency trains known to make fast muscles slow reduced the HIF-1α level of the fast extensor digitorum longus (EDL) muscle by 44%. Nuclear protein extracts from normal EDL contained 2.3-fold more HIF-1α and 4-fold more HIF-1ß than the slow soleus muscle, while von-Hippel-Lindau protein was 4.8-fold higher in slow muscles. mRNA displayed a reciprocal pattern; thus FIH-1 mRNA was almost 2-fold higher in fast muscle, while the HIF-1α level was half, and consequently protein/mRNA ratio for HIF-1α was more than 4-fold higher in the fast muscle, suggesting that HIF-1α is strongly suppressed post-transcriptionally in slow muscles.When HIF-1α was overexpressed for 14 days after somatic gene transfer in adult rats, a slow-to-fast transformation was observed, encompassing an increase in fibre cross sectional area, oxidative enzyme activity and myosin heavy chain. The latter was shown to be regulated at the mRNA level in C2C12 myotubes.

Epigallocatechin gallate (EGCG) mimics insulin action on the transcription factor FOXO1a and elicits cellular responses in the presence and absence of insulin.

The green tea flavonoid epigallocatechin gallate (EGCG) is one of several compounds that have been reported to have insulin-like glucose-lowering properties in mammals. EGCG is understood to act at least in part by repression of gluconeogenic genes such as phosphoenolpyruvate carboxykinase but the transcription factors that are targeted to achieve this are unknown. We show here that EGCG induces phosphorylation of insulin-sensitive residues on the transcription factor FOXO1a. Like insulin, EGCG induced FOXO1a phosphorylation is abolished by the PtdIns 3-kinase inhibitor LY294002 but not by PD98059 (an inhibitor of mitogen-activated protein kinase cascade) or by rapamycin (an inhibitor of signalling to p70 S6 kinase). EGCG differs from insulin and IGF-1 however, in that its induction of FOXO1a phosphorylation is sensitive to scavengers of reactive oxygen species (ROS). These results indicate that EGCG exerts its insulin mimetic effects at least in part by phosphorylation of the FOXOs through a mechanism that is similar but not identical to insulin and IGF-1 induced FOXO phosphorylation. Our results suggest that agents acting in the manner of EGCG may be useful antidiabetic agents.

Black tea polyphenols mimic insulin/insulin-like growth factor-1 signalling to the longevity factor FOXO1a.

In vertebrates and invertebrates, relationships between diet and health are controlled by a conserved signalling pathway responsive to insulin-like ligands. In invertebrate models for example, forkhead transcription factor family O (FOXO) transcription factors in this pathway regulate the rate of aging in response to dietary cues, and in vertebrates, obesity and age-induced deficits in the same pathway are thought to contribute to dysregulation of hepatic gluconeogenesis through genes such as phosphoenolpyruvate carboxykinase (PEPCK). Recently, we have begun to screen for dietary constituents capable of regulating this pathway in our cell culture model. Here, we identify three black tea theaflavins, theaflavin 3-O-gallate, theaflavin 3'-O-gallate, theaflavin 3,3'di-O-gallate and thearubigins as novel mimics of insulin/IGF-1 action on mammalian FOXO1a, PEPCK and moreover we provide evidence that the effects on this pathway of the green tea constituent (-)-epigallocatechin gallate depend on its ability to be converted into these larger structures. With the exception of water, tea is the most popular drink globally, but despite this, little is known about the biological availability of black tea polyphenols in vivo or the molecular target(s) mediating the effects presented here. Further investigation in these two areas might provide insight into how age-related metabolic disease may be deferred.