Increased liver glycogen levels enhance exercise capacity in mice

Iliana López-Soldado,Joan J Guinovart,Jordi Duran

doi:10.1016/j.jbc.2021.100976

Abstract

Muscle glycogen depletion has been proposed as one of the main causes of fatigue during exercise. However, few studies have addressed the contribution of liver glycogen to exercise performance. Using a low-intensity running protocol, here, we analyzed exercise capacity in mice overexpressing protein targeting to glycogen (PTG) specifically in the liver (PTGOE mice), which show a high concentration of glycogen in this organ. PTGOE mice showed improved exercise capacity, as determined by the distance covered and time ran in an extenuating endurance exercise, compared with control mice. Moreover, fasting decreased exercise capacity in control mice but not in PTGOE mice. After exercise, liver glycogen stores were totally depleted in control mice, but PTGOE mice maintained significant glycogen levels even in fasting conditions. In addition, PTGOE mice displayed an increased hepatic energy state after exercise compared with control mice. Exercise caused a reduction in the blood glucose concentration in control mice that was less pronounced in PTGOE mice. No changes were found in the levels of blood lactate, plasma free fatty acids, or β-hydroxybutyrate. Plasma glucagon was elevated after exercise in control mice, but not in PTGOE mice. Exercise-induced changes in skeletal muscle were similar in both genotypes. These results identify hepatic glycogen as a key regulator of endurance capacity in mice, an effect that may be exerted through the maintenance of blood glucose levels.

Highlights

Carbohydrate and fat are the main substrates used during prolonged endurance-type exercise [11,12,13]
overexpressing PTG specifically in the liver (PTGOE) mice showed an increase in hepatic glycogen compared with control mice both in fed and fasting conditions (Fig. 1A), as previously described [27]
We sought to determine whether the increased exercise capacity observed in PTGOE mice is associated with changes in some of the main genes related to muscle metabolism

Summary

Results

To study the role of increased liver glycogen storage in endurance capacity, we generated PTGOE mice (see Experimental procedures). We found that exercise and fasting increased hepatic TAG concentration in fed control and PTGOE mice (Fig. 2C). Exercise increased plasma FFAs and β-hydroxybutyrate levels in both genotypes (Fig. 3, C and D). We sought to determine whether the increased exercise capacity observed in PTGOE mice is associated with changes in some of the main genes related to muscle metabolism. Exercise induced an increase in the expression of hexokinase-2 (Fig. 6C), Pgc1α (Fig. 6D), and Nr4a3 (Fig. 6E) in muscle under fed and fasting conditions, but there were no differences between the genotypes. Exercise upregulated the expression of uncoupling protein 3 (Fig. 6F) and muscle RING-finger protein-1 (Fig. 6G) under fed but not under fasting conditions because fasting already induced an increase in these genes

Discussion

C PTG C PTG Sedentary Exercise

Experimental procedures