Rasmus Sjørup Biensø:
Regulation of PDH, GS and insulin signalling in skeletal muscle; effect of physical activity level and inflammation

Date: 31-01-2014    Supervisor: Henriette Pilegaard

The aims of the present thesis were to investigate 1) The impact of physical inactivity on insulinstimulated Akt, TBC1D4 and GS regulation in human skeletal muscle, 2) The impact of exercise training on glucose-mediated regulation of PDH and GS in skeletal muscle in elderly men, 3) The impact of inflammation on resting and exercise-induced PDH regulation in human skeletal muscle and 4) The effect of IL-6 on PDH regulation in mouse skeletal muscle.

Study I demonstrated that bed rest–induced insulin resistance was associated with reduced insulinstimulated GS activity and Akt signaling as well as decreased protein level of HKII and GLUT4 in skeletal muscle. Iαn addition, the ability of acute exercise to increase insulin-stimulated glucose extraction was maintained after 7 days of bed rest. However, acute exercise after bed rest did not fully normalize the ability of skeletal muscle to extract glucose to the level seen when exercise was performed before bed rest.

Study II demonstrated that exercise training-improved glucose regulation in elderly healthy subjects was associated with increased HKII, GLUT4, Akt2, PDK2, GS and PDH-E1α protein content. Moreover, exercise training resulted in an enhanced response of TBC1D4 and GS and a reduced PDHa activity in response to glucose intake relative to before training.

Study III demonstrated that LPS-induced inflammation with elevated plasma TNFα concentration did not affect resting or exercise-induced AMPK and PDH regulation in human skeletal muscle. Study IV demonstrated that an IL-6 injection reduced PDHa activity in skeletal muscle from fed mice and increased the PDHa activity in skeletal muscle from fasted mice without any change in phosphorylation level. An IL-6 injection increased AMPK and ACC phosphorylation in mouse skeletal muscle only in the fasted state. In addition, the effects of IL-6 on PDH were rather modest relative to the changes observed with fasting.

In conclusion, 1) decreased glucose transport/phosphorylation and decreased non-oxidative glucose metabolism seemed to contribute to the decreased skeletal muscle glucose extraction with physical inactivity in humans, and physical inactivity did not affect the ability of exercise to enhance insulinmediated skeletal muscle glucose extraction. 2) Exercise training-improved glucose handling in aged human skeletal muscle was associated with increased content of key proteins in glucose metabolism and acute molecular changes towards improved glucose uptake and storage. 3) Shortterm inflammation did not seem to influence resting or exercise-induced fat and carbohydrate utilization in human skeletal muscle. 4) IL-6 may regulate the PDHa activity in mouse skeletal muscle, but the effect seems to depend on the energy state of the muscle, and AMPK may be involved in the fasted state.