Abstract
The 5'-AMP-activated protein kinase (AMPK) is considered "a metabolic master-switch" in skeletal muscle reducing ATP- consuming processes whilst stimulating ATP regeneration. Within recent years, AMPK has also been proposed as a potential target to attenuate insulin resistance, although the exact role of AMPK is not well understood. Here we hypothesized that mice lacking α2AMPK activity in muscle would be more susceptible to develop insulin resistance associated with ageing alone or in combination with high fat diet. Young (∼4 month) or old (∼18 month) wild type and muscle specific α2AMPK kinase-dead mice on chow diet as well as old mice on 17 weeks of high fat diet were studied for whole body glucose homeostasis (OGTT, ITT and HOMA-IR), insulin signaling and insulin-stimulated glucose uptake in muscle. We demonstrate that high fat diet in old mice results in impaired glucose homeostasis and insulin stimulated glucose uptake in both the soleus and extensor digitorum longus muscle, coinciding with reduced insulin signaling at the level of Akt (pSer473 and pThr308), TBC1D1 (pThr590) and TBC1D4 (pThr642). In contrast to our hypothesis, the impact of ageing and high fat diet on insulin action was not worsened in mice lacking functional α2AMPK in muscle. It is concluded that α2AMPK deficiency in mouse skeletal muscle does not cause muscle insulin resistance in young and old mice and does not exacerbate obesity-induced insulin resistance in old mice suggesting that decreased α2AMPK activity does not increase susceptibility for insulin resistance in skeletal muscle.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases / genetics
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AMP-Activated Protein Kinases / metabolism*
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Aging / metabolism*
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Animals
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Area Under Curve
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Blood Glucose
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Body Composition
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Diet, High-Fat / adverse effects*
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GTPase-Activating Proteins / metabolism
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Glucose Tolerance Test
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Glucose Transporter Type 4 / metabolism
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Hexokinase / metabolism
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Homeostasis
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Insulin / physiology*
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Insulin Resistance*
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Male
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Mice
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Mice, Inbred C57BL
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Muscle Proteins / metabolism
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Muscle, Skeletal / metabolism
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Phosphorylation
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Protein Processing, Post-Translational
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Proto-Oncogene Proteins c-akt / metabolism
Substances
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Blood Glucose
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GTPase-Activating Proteins
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Glucose Transporter Type 4
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Insulin
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Muscle Proteins
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Slc2a4 protein, mouse
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Tbc1d4 protein, mouse
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Hexokinase
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AMPK alpha2 subunit, mouse
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Proto-Oncogene Proteins c-akt
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AMP-Activated Protein Kinases
Grants and funding
This work was supported by grants from the Lundbaek Foundation, Denmark, The Danish Medical Research Council, Denmark, The Danish Agency of Science, Technology and Innovation, The Danish Ministry of Food, Agriculture and Fisheries, The Novo Nordisk Foundation, and the Danish Diabetes Association. The Molecular Physiology group, Department of Nutrition, Exercise and Sports is part of the August Krogh Centre and the UNIversal Kit Project: Food, Fitness & Pharma for Health and Disease, supported by the Danish Ministry of Science, Technology and Innovation. TEJ and JTT were supported by a postdoctoral fellowship from The Danish Agency for Science, Technology and Innovation. JJ was supported by a research fellowship from The Alfred Benzon Foundation. PS was supported by the Nordea Foundation (Healthy Aging Grant). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center, based at the University of Copenhagen, Denmark and partially funded by an unconditional donation from the Novo Nordisk Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.