Molecular mechanisms governing contraction-induced metabolic responses and skeletal muscle reprogramming
Author: Glund, Stephan
Date: 2007-12-14
Location: Föreläsningssalen Atrium, Nobels väg 12b, Karolinska Institutet, Solna
Time: 13.00
Department: Institutionen för molekylär medicin och kirurgi / Department of Molecular Medicine and Surgery
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thesis.pdf (789.3Kb)
Abstract
Physical exercise enhances skeletal muscle responsiveness to insulin and
regulates metabolism by an insulin-independent mechanism. Elucidation of
contraction-mediated molecular mechanisms is imperative for a better
understanding of skeletal muscle metabolism and function, and may lead to
the identification or validation of possible drug targets for the
prevention or treatment of metabolic disorders. This thesis focuses on
the role of AMPK and Interleukin (IL)-6 in skeletal muscle metabolism,
because AMPK activity and skeletal muscle IL-6 release are increased
during skeletal muscle contraction.
Contraction-mediated AMPK activity in white glycolytic extensor digitorum
longus (EDL) muscle was inversely coupled to skeletal muscle glycogen
content in wild-type and transgenic mice expressing a mutated form of the
AMPKgamma3 isoform (Tg-Prkag3225Q), but not AMPKgamma3 knockout (KO)
mice, highlighting a role for the AMPKgamma3 isoform in energy sensing
during muscle contraction. Isolated skeletal muscle from Tg-Prkag3225Q
and AMPKgamma3 KO mice were fatigue-resistant and fatigue-prone,
respectively; and work performance was coupled to glycogen content in all
mouse models, highlighting a role for AMPKgamma3 in skeletal muscle
ergogenics by controlling glycogen levels. Hypoxia-mediated glucose
transport was partly reduced in skeletal muscle from AMPKgamma3 KO mice.
AICAR and contraction-mediated phosphorylation of the Akt substrate,
AS160, was dependent on functional AMPK signaling, providing direct
genetic evidence that AS160 is a phosphorylation target of AMPK.
IL-6 is released from contracting human skeletal muscle. We provide
evidence that IL-6 release is greater from oxidative, compared to
glycolytic skeletal muscle. Basal IL-6 release was increased from
oxidative soleus muscle of AMPKá1 KO and AMPKá2 kinasedead mice. Thus, we
provide evidence for a role of AMPK in the basal regulation of IL-6
release from isolated oxidative skeletal muscle. Furthermore,
AICAR-mediated suppression of basal IL-6 mRNA production and release was
independent of functional AMPK signaling. Autocrine mechanisms may play a
role in basal IL-6 release from isolated skeletal muscle.
IL-6 concentrations in the contracting skeletal muscle may exceed serum
levels. We therefore investigated the direct effect of IL-6 on human
skeletal muscle by exposing primary human skeletal muscle cells and
isolated human skeletal muscle strips to IL-6. IL-6-exposure directly
influences glucose metabolism, as determined by increased glucose
transport and glucose incorporation into glycogen. In primary human
skeletal muscle cells, IL-6-exposure activated components of the
canonical insulin signaling cascade. Glucose incorporation into glycogen
was sensitive to phosphatidylinositol (PI) 3-kinase inhibition. In
contrast, IL-6-exposure was without effect on insulin signaling in
isolated human skeletal muscle, and increased glucose metabolism was
observed, concomitant with a trend for increased phosphorylation of AMPK.
In primary human muscle cells, the IL-6-mediated enhancement of fatty
acid oxidation was attenuated by silencing AMPKá isoforms. Long-term
IL-6-exposure of primary myotubes enhanced growth and differentiation and
increased the expression of genes involved in muscle metabolism.
In conclusion, this thesis work provides evidence that AMPK and IL-6 are
central players in the regulation of contraction-mediated effects on
metabolic responses in skeletal muscle. In addition to the involvement in
acute regulation of metabolism, IL-6 may also participate in skeletal
muscle adaptation to exercise.
List of papers:
I. Barnes BR, Glund S, Long YC, Hjälm G, Andersson L, Zierath JR (2005). "5-AMP-activated protein kinase regulates skeletal muscle glycogen content and ergogenics." FASEB J 19(7): 773-9
Pubmed
II. Treebak JT, Glund S, Deshmukh A, Klein DK, Long YC, Jensen TE, Jørgensen SB, Viollet B, Andersson L, Neumann D, Wallimann T, Richter EA, Chibalin AV, Zierath JR, Wojtaszewski JF (2006). "AMPK-mediated AS160 phosphorylation in skeletal muscle is dependent on AMPK catalytic and regulatory subunits." Diabetes 55(7): 2051-8
Pubmed
III. Glund S, Treebak JT, Long YC, Barres R, Viollet B, Wojtaszewski JF, Zierath JR (2007). "Role of AMPK in basal and AICAR-mediated IL-6 release from isolated mouse skeletal muscle." (Submitted)
IV. Glund S, Deshmukh A, Long YC, Moller T, Koistinen HA, Caidahl K, Zierath JR, Krook A (2007). "Interleukin-6 directly increases glucose metabolism in resting human skeletal muscle." Diabetes 56(6): 1630-7. Epub 2007 Mar 15
Pubmed
V. Al-Khalili L, Bouzakri K, Glund S, Lönnqvist F, Koistinen HA, Krook A (2006). "Signaling specificity of interleukin-6 action on glucose and lipid metabolism in skeletal muscle." Mol Endocrinol 20(12): 3364-75. Epub 2006 Aug 31
Pubmed
I. Barnes BR, Glund S, Long YC, Hjälm G, Andersson L, Zierath JR (2005). "5-AMP-activated protein kinase regulates skeletal muscle glycogen content and ergogenics." FASEB J 19(7): 773-9
Pubmed
II. Treebak JT, Glund S, Deshmukh A, Klein DK, Long YC, Jensen TE, Jørgensen SB, Viollet B, Andersson L, Neumann D, Wallimann T, Richter EA, Chibalin AV, Zierath JR, Wojtaszewski JF (2006). "AMPK-mediated AS160 phosphorylation in skeletal muscle is dependent on AMPK catalytic and regulatory subunits." Diabetes 55(7): 2051-8
Pubmed
III. Glund S, Treebak JT, Long YC, Barres R, Viollet B, Wojtaszewski JF, Zierath JR (2007). "Role of AMPK in basal and AICAR-mediated IL-6 release from isolated mouse skeletal muscle." (Submitted)
IV. Glund S, Deshmukh A, Long YC, Moller T, Koistinen HA, Caidahl K, Zierath JR, Krook A (2007). "Interleukin-6 directly increases glucose metabolism in resting human skeletal muscle." Diabetes 56(6): 1630-7. Epub 2007 Mar 15
Pubmed
V. Al-Khalili L, Bouzakri K, Glund S, Lönnqvist F, Koistinen HA, Krook A (2006). "Signaling specificity of interleukin-6 action on glucose and lipid metabolism in skeletal muscle." Mol Endocrinol 20(12): 3364-75. Epub 2006 Aug 31
Pubmed
Issue date: 2007-11-23
Rights:
Publication year: 2007
ISBN: 978-91-7357-436-5
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