Molecular mechanisms governing contraction-induced metabolic responses and skeletal muscle reprogramming
Year: 2007
Type: dissertation
Abstract: Physical exercise enhances skeletal muscle responsiveness to insulin and\nregulates metabolism by an insulin-independent mechanism. Elucidation of\ncontraction-mediated molecular mechanisms is imperative for a better\nunderstanding of skeletal muscle metabolism and function, and may lead to\nthe identification or validation of possible drug targets for the\nprevention or treatment of metabolic disorders. This thesis focuses on\nthe role of AMPK and Interleukin (IL)-6 in skeletal muscle metabolism,\nbecause AMPK activity and skeletal muscle IL-6 release are increased\nduring skeletal muscle contraction.\n\nContraction-mediated AMPK activity in white glycolytic extensor digitorum\nlongus (EDL) muscle was inversely coupled to skeletal muscle glycogen\ncontent in wild-type and transgenic mice expressing a mutated form of the\nAMPKgamma3 isoform (Tg-Prkag3225Q), but not AMPKgamma3 knockout (KO)\nmice, highlighting a role for the AMPKgamma3 isoform in energy sensing\nduring muscle contraction. Isolated skeletal muscle from Tg-Prkag3225Q\nand AMPKgamma3 KO mice were fatigue-resistant and fatigue-prone,\nrespectively; and work performance was coupled to glycogen content in all\nmouse models, highlighting a role for AMPKgamma3 in skeletal muscle\nergogenics by controlling glycogen levels. Hypoxia-mediated glucose\ntransport was partly reduced in skeletal muscle from AMPKgamma3 KO mice.\nAICAR and contraction-mediated phosphorylation of the Akt substrate,\nAS160, was dependent on functional AMPK signaling, providing direct\ngenetic evidence that AS160 is a phosphorylation target of AMPK.\n\nIL-6 is released from contracting human skeletal muscle. We provide\nevidence that IL-6 release is greater from oxidative, compared to\nglycolytic skeletal muscle. Basal IL-6 release was increased from\noxidative soleus muscle of AMPKá1 KO and AMPKá2 kinasedead mice. Thus, we\nprovide evidence for a role of AMPK in the basal regulation of IL-6\nrelease from isolated oxidative skeletal muscle. Furthermore,\nAICAR-mediated suppression of basal IL-6 mRNA production and release was\nindependent of functional AMPK signaling. Autocrine mechanisms may play a\nrole in basal IL-6 release from isolated skeletal muscle.\n\nIL-6 concentrations in the contracting skeletal muscle may exceed serum\nlevels. We therefore investigated the direct effect of IL-6 on human\nskeletal muscle by exposing primary human skeletal muscle cells and\nisolated human skeletal muscle strips to IL-6. IL-6-exposure directly\ninfluences glucose metabolism, as determined by increased glucose\ntransport and glucose incorporation into glycogen. In primary human\nskeletal muscle cells, IL-6-exposure activated components of the\ncanonical insulin signaling cascade. Glucose incorporation into glycogen\nwas sensitive to phosphatidylinositol (PI) 3-kinase inhibition. In\ncontrast, IL-6-exposure was without effect on insulin signaling in\nisolated human skeletal muscle, and increased glucose metabolism was\nobserved, concomitant with a trend for increased phosphorylation of AMPK.\nIn primary human muscle cells, the IL-6-mediated enhancement of fatty\nacid oxidation was attenuated by silencing AMPKá isoforms. Long-term\nIL-6-exposure of primary myotubes enhanced growth and differentiation and\nincreased the expression of genes involved in muscle metabolism.\n\nIn conclusion, this thesis work provides evidence that AMPK and IL-6 are\ncentral players in the regulation of contraction-mediated effects on\nmetabolic responses in skeletal muscle. In addition to the involvement in\nacute regulation of metabolism, IL-6 may also participate in skeletal\nmuscle adaptation to exercise.
Source: Figshare
Author: Stephan Glund
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1525144977