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We investigated the effects of chronic pre-exercise acetate administration on body weight and metabolic adaptations to endurance training in ICR mice fed with either a normal fat diet (NFD) or high fat diet (HFD), respectively. Mice were divided into a control group (Con), an acetate group (Ace), a training group (Tra), and an acetate+training group (Ace+Tra) with NFD or HFD, respectively. Mice received orally either water or acetate (72 mg/kg body weight/day) for 4 weeks. The mice in the training group were subjected to training using a treadmill (20–25 m/min×60 min, 5 times/week) immediately after administration. As a result, in the NFD mice, there was no effect of acetate in any of the measurements. In the HFD mice, the final body weight in the Ace, Tra and Ace+Tra groups was significantly lower than the Con group. Moreover, the acetate treatment tended to decrease blood glucose concentration at rest. Gastrocnemius muscle glycogen concentration in the Ace+Tra group was significantly higher than that of the Ace and Tra groups. Unexpectedly, a significant negative main effect of acetate treatment in the maximal activity of β-HAD was observed, though the endurance training increased enzyme activity of citrate synthase in the plantaris muscle. These findings show the possibility that acetate treatment with endurance training shifts the metabolic characteristics of mice toward a carbohydrate metabolism against a lipid metabolism with the HFD condition, but not with the NFD condition.

We investigated the effects of β-hydroxybutyrate (β-HB), the most abundant type of ketone body in mammals, on postexercise glycogen recovery in skeletal muscle by using an in vitro experimental model. Male ICR mice swam for 60 min and then their epitrochlearis muscles were removed and incubated with either physiological levels of glucose (8 mmol/L) and insulin (60 μU/mL) or glucose and insulin plus 1, 2, or 4 mmol/L of sodium β-HB. Four millimoles per liter β-HB had a significant positive effect on glycogen repletion in epitrochlearis muscle at 120 min after exercise (p < 0.01), while 2 mmol/L of β-HB showed a tendency to increase the glycogen level (p < 0.09), and 1 mmol/L of β-HB had no significant effect. We further investigated the effect of 4 mmol/L β-HB treatment on the signaling cascade related to glycogen repletion in the epitrochlearis muscles throughout a 120-min recovery period. After incubating the muscles in 4 mmol/L of β-HB for 15 min postexercise, the Akt substrate of 160 kDa Thr642(p < 0.05) and Akt Thr308(p < 0.05) phosphorylations were significantly increased compared with the control treatment. At the same time point, 5′-AMP–activated protein kinase and acetyl-coenzyme A carboxylase phosphorylations were significantly lower (p < 0.05) in the epitrochlearis muscle incubated with 4 mmol/L of β-HB than in the control muscle. Our results demonstrate that postexercise 4 mmol/L β-HB administration enhanced glycogen repletion in epitrochlearis muscle. Four millimoles per liter β-HB treatment was associated with alternation of the phosphorylated status of several proteins involved in glucose uptake and metabolic/energy homeostasis at the early stage of postexercise.

To identify factors that influence post-exercise muscle glycogen repletion, we compared the glycogen recovery after level running with downhill running, an experimental model of impaired post-exercise glycogen recovery. Male Institute of Cancer Research (ICR) mice performed endurance level running (no inclination) or downhill running (−5° inclination) on a treadmill. In Experiment 1, to determine whether these two types of exercise resulted in different post-exercise glycogen repletion patterns, tissues were harvested immediately post-exercise or 2 days post-exercise. Compared to the control (sedentary) group, level running induced significant glycogen supercompensation in the soleus muscle at 2 days post-exercise (p = 0.002). Downhill running did not induce glycogen supercompensation. In Experiment 2, mice were orally administered glucose 1 day post-exercise; this induced glycogen supercompensation in soleus and plantaris muscle only in the level running group (soleus: p = 0.005, plantaris: p = 0.003). There were significant positive main effects of level running compared to downhill running on the plasma insulin (p = 0.017) and C-peptide concentration (p = 0.011). There was no difference in the glucose transporter 4 level or the phosphorylated states of proteins related to insulin signaling and metabolism in skeletal muscle. The level running group showed significantly higher hexokinase 2 (HK2) protein content in both soleus (p = 0.046) and plantaris muscles (p =0.044) at 1 day after exercise compared to the downhill running group. Our findings suggest that post-exercise skeletal muscle glycogen repletion might be partly influenced by plasma insulin and skeletal muscle HK2 protein levels.

We investigated the effects of nutrient intake timing on glycogen accumulation and its related signals in skeletal muscle after an exercise that did not induce large glycogen depletion. Male ICR mice ran on a treadmill at 25 m/min for 60 min under a fed condition. Mice were orally administered a solution containing 1.2 mg/g carbohydrate and 0.4 mg/g protein or water either immediately (early nutrient, EN) or 180 min (late nutrient, LN) after the exercise. Tissues were harvested at 30 min after the oral administration. No significant difference in blood glucose or plasma insulin concentrations was found between the EN and LN groups. The plantaris muscle glycogen concentration was significantly (p &lt, 0.05) higher in the EN group&mdash, but not in the LN group&mdash, compared to the respective time-matched control group. Akt Ser473 phosphorylation was significantly higher in the EN group than in the time-matched control group (p &lt, 0.01), while LN had no effect. Positive main effects of time were found for the phosphorylations in Akt substrate of 160 kDa (AS160) Thr642 (p &lt, 0.05), 5'-AMP-activated protein kinase (AMPK) Thr172 (p &lt, 0.01), and acetyl-CoA carboxylase Ser79 (p &lt, 0.01), however, no effect of nutrient intake was found for these. We showed that delayed nutrient intake could not increase muscle glycogen after endurance exercise which did not induce large glycogen depletion. The results also suggest that post-exercise muscle glycogen accumulation after nutrient intake might be partly influenced by Akt activation. Meanwhile, increased AS160 and AMPK activation by post-exercise fasting might not lead to glycogen accumulation.

We investigated the effect of royal jelly (RJ), a natural secretion from worker bees, on the endurance training-induced mitochondrial adaptations in skeletal muscles of ICR mice. Mice received either RJ (1.0 mg/g body weight) or distilled water for three weeks. The mice in the training group were subjected to endurance training (20 m/min, 60 min, 5 times/week). There was a main effect of endurance training on the maximal activities of the mitochondrial enzymes, citrate synthase (CS), and &beta, hydroxyacyl coenzyme Adehydrogenase (&beta, HAD), in the plantaris and tibialis anterior (TA) muscles, while no effect of RJ treatment was observed. In the soleus muscle, CS and &beta, HAD maximal activities were significantly increased by endurance training in the RJ-treated group, while there was no effect of training in the control group. Furthermore, we investigated the effects of acute RJ treatment on the signaling cascade involved in mitochondrial biogenesis. In the soleus, phosphorylation of 5&prime, AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) were additively increased by a single RJ treatment and endurance exercise, while only an exercise effect was found in the plantaris and TA muscles. These results indicate that the RJ treatment induced mitochondrial adaptation with endurance training by AMPK activation in the soleus muscles of ICR mice.