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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.