Rieko Oshima

Caffeine and contraction synergistically stimulate 5′‐AMP‐activated protein kinase and insulin‐independent glucose transport in rat skeletal muscle

5′‐Adenosine monophosphate‐activated protein kinase (AMPK) has been identified as a key mediator of contraction‐stimulated insulin‐independent glucose transport in skeletal muscle. Caffeine acutely stimulates AMPK in resting skeletal muscle, but it is unknown whether caffeine affects AMPK in contracting muscle. Isolated rat epitrochlearis muscle was preincubated and then incubated in the absence or presence of 3 mmol/L caffeine for 30 or 120 min. Electrical stimulation (ES) was used to evoke tetanic contractions during the last 10 min of the incubation period. The combination of caffeine plus contraction had additive effects on AMPKα Thr172 phosphorylation, α‐isoform‐specific AMPK activity, and 3‐O‐methylglucose (3MG) transport. In contrast, caffeine inhibited basal and contraction‐stimulated Akt Ser473 phosphorylation. Caffeine significantly delayed muscle fatigue during contraction, and the combination of caffeine and contraction additively decreased ATP and phosphocreatine contents. Caffeine did not affect resting tension. Next, rats were given an intraperitoneal injection of caffeine (60 mg/kg body weight) or saline, and the extensor digitorum longus muscle was dissected 15 min later. ES of the sciatic nerve was performed to evoke tetanic contractions for 5 min before dissection. Similar to the findings from isolated muscles incubated in vitro, the combination of caffeine plus contraction in vivo had additive effects on AMPK phosphorylation, AMPK activity, and 3MG transport. Caffeine also inhibited basal and contraction‐stimulated Akt phosphorylation in vivo. These findings suggest that caffeine and contraction synergistically stimulate AMPK activity and insulin‐independent glucose transport, at least in part by decreasing muscle fatigue and thereby promoting energy consumption during contraction.

Heat stress acutely activates insulin‐independent glucose transport and 5′‐AMP‐activated protein kinase prior to an increase in HSP72 protein in rat skeletal muscle

Heat stress (HS) stimulates heat shock protein (HSP) 72 mRNA expression, and the period after an increase in HSP72 protein is characterized by enhanced glucose metabolism in skeletal muscle. We have hypothesized that, prior to an increase in the level of HSP72 protein, HS activates glucose metabolism by acutely stimulating 5′‐AMP‐activated protein kinase (AMPK). Rat epitrochlearis muscle was isolated and incubated either with or without HS (42°C) for 10 and 30 min. HS for 30 min led to an increase in the level of Hspa1a and Hspa1b mRNA but did not change the amount of HSP72 protein. However, HS for both 10 and 30 min led to a significant increase in the rate of 3‐O‐methyl‐d‐glucose (3MG) transport, and the stimulatory effect of 3MG transport was completely blocked by cytochalasin B. HS‐stimulated 3MG transport was also inhibited by dorsomorphin but not by wortmannin. HS led to a decrease in the concentration of ATP, phosphocreatine, and glycogen, to an increase in the level of phosphorylation of AMPKα Thr172, and to an increase in the activity of both AMPKα1 and AMPKα2. HS did not affect the phosphorylation status of insulin receptor signaling or Ca2+/calmodulin‐dependent protein kinase II. These results suggest that HS acts as a rapid stimulator of insulin‐independent glucose transport, at least in part by stimulating AMPK via decreased energy status. Although further research is warranted, heat treatment of skeletal muscle might be a promising method to promote glucose metabolism acutely.

Coptidis Rhizoma Water Extract Stimulates 5′-AMP-Activated Protein Kinase in Rat Skeletal Muscle

Aim Coptidis Rhizoma (CR), the dried rhizomes of Asian herbs (including Coptis chinensis Franch), has been used to treat diabetes mellitus for thousands of years. We explored the possibility that CR acts directly on skeletal muscle, the major organ responsible for glucose homeostasis, and activates 5′-AMP-activated protein kinase (AMPK), a signaling intermediary leading to metabolic enhancement of skeletal muscle.

Regulatory Mechanism of Skeletal Muscle Glucose Transport by Phenolic Acids

Type 2 diabetes mellitus (T2DM) is one of the most severe public health problems in the world. In recent years, evidences show a commonness of utilization of alternative medicines such as phytomedicine for the treatment of T2DM. Phenolic acids are the most common compounds in non-flavonoid group of phenolic compounds and have been suggested to have a potential to lower the risk of T2DM. Skeletal muscle is the major organ that contributes to the pathophysiology of T2DM. Studies have shown that several phenolic acids (caffeic acid, chlorogenic acid, gallic acid, salicylic acid, p-coumaric acid, ferulic acid, sinapic acid) have antidiabetic effects, and these compounds have been implicated in the regulation of skeletal muscle glucose metabolism, especially glucose transport. Glucose transport is a major regulatory step for whole-body glucose disposal, and the glucose transport processes are regulated mainly through two different systems: insulin-dependent and insulinindependent mechanism. In this chapter, we reviewed recent experimental evidences linking phenolic acids to glucose metabolism focusing on insulin-dependent and insulin-independent glucose transport systems and the upstream signaling events in skeletal muscle.