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Akt (protein kinase B) isoform phosphorylation and signaling downstream of mTOR (mammalian target of rapamycin) in denervated atrophic and hypertrophic mouse skeletal muscle.
Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
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2012 (English)In: Journal of Molecular Signaling, ISSN 1750-2187, E-ISSN 1750-2187, Vol. 7, no June, Article ID: 7- p.Article in journal (Refereed) Published
Abstract [en]

ABSTRACT: BACKGROUND: The present study examines the hypothesis that Akt (protein kinase B)/mTOR (mammalian target of rapamycin) signaling is increased in hypertrophic and decreased in atrophic denervated muscle. Protein expression and phosphorylation of Akt1, Akt2, glycogen synthase kinase-3beta (GSK-3beta), eukaryotic initiation factor 4E binding protein 1 (4EBP1), 70 kD ribosomal protein S6 kinase (p70S6K1) and ribosomal protein S6 (rpS6) were examined in six-days denervated mouse anterior tibial (atrophic) and hemidiaphragm (hypertrophic) muscles. RESULTS: In denervated hypertrophic muscle expression of total Akt1, Akt2, GSK-3beta, p70S6K1 and rpS6 proteins increased 2-10 fold whereas total 4EBP1 protein remained unaltered. In denervated atrophic muscle Akt1 and Akt2 total protein increased 2-16 fold. A small increase in expression of total rpS6 protein was also observed with no apparent changes in levels of total GSK-3beta, 4EBP1 or p70S6K1 proteins. The level of phosphorylated proteins increased 3-13 fold for all the proteins in hypertrophic denervated muscle. No significant changes in phosphorylated Akt1 or GSK-3beta were detected in atrophic denervated muscle. The phosphorylation levels of Akt2, 4EBP1, p70S6K1 and rpS6 were increased 2-18 fold in atrophic denervated muscle. CONCLUSIONS: The results are consistent with increased Akt/mTOR signaling in hypertrophic skeletal muscle. Decreased levels of phosphorylated Akt (S473/S474) were not observed in denervated atrophic muscle and results downstream of mTOR indicate increased protein synthesis in denervated atrophic anterior tibial muscle as well as in denervated hypertrophic hemidiaphragm muscle. Increased protein degradation, rather than decreased protein synthesis, is likely to be responsible for the loss of muscle mass in denervated atrophic muscles.

Place, publisher, year, edition, pages
2012. Vol. 7, no June, Article ID: 7- p.
National Category
Cell and Molecular Biology Cell Biology Neurosciences
Research subject
Natural Science, Biomedical Sciences
Identifiers
URN: urn:nbn:se:lnu:diva-20341DOI: 10.1186/1750-2187-7-7PubMedID: 22657251Scopus ID: 2-s2.0-84861707979OAI: oai:DiVA.org:lnu-20341DiVA: diva2:536281
Available from: 2012-06-21 Created: 2012-06-21 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Signaling factors related to atrophy and hypertrophy in denervated skeletal muscle
Open this publication in new window or tab >>Signaling factors related to atrophy and hypertrophy in denervated skeletal muscle
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The human body consists of about 40 % skeletal muscles which control the body’s movement, ability to stand up, force generation, locomotion, heat production and are also the body’s protein reservoir. Muscle mass is controlled by the relationship between protein synthesis and protein degradation. Atrophy, a decrease in muscle mass, can be trigged by disuse, immobilization, inflammation and cancer. Hypertrophy, an increase in muscle mass, can occur after increased mechanical load, high usage and/or anabolic stimulation. The aim of this thesis was to investigate changes in expression and post translational modifications of some factors involved in the regulation of protein synthesis and protein degradation in 6-days denervated atrophic hind-limb muscles (anterior tibial and pooled gastrocnemius and soleus muscles) and in 6-days denervated hypertrophic hemidiaphragm muscle in mice. Protein expression and post translational modifications were studied semi-quantitatively using Western blots with whole muscle homogenates and separated nuclear and cytosolic fractions from both innervated and denervated muscles.  An increase in protein synthesis after denervation in both atrophic and hypertrophic muscles was suggested after studies of factors downstream of mTOR (paper I).  Other results suggest that FoxO1 and MuRF1 (paper II) participate in the tissue remodeling that occurs after denervation. A differential response of MK2 phosphorylation in denervated hypertrophic and atrophic muscles was confirmed (paper III). An increase in phosphorylation of the MK2 substrate Hsp 25 in all denervated muscles studied (paper III) indicates that other factors than MK2 are involved in regulating this phosphorylation. eIF4G phosphorylation at S1108 was investigated (paper IV) and a decrease was observed in atrophic muscle but an increase in hypertrophic muscle. The results in this thesis suggest that there are several factors that control protein degradation and protein synthesis in denervated atrophic and hypertrophic skeletal muscles. This is an intricate labyrinth with many different cell signaling factors, the function of which are still far from fully understood.

Place, publisher, year, edition, pages
Växjö: Linnaeus University Press, 2014. 96 p.
Series
Linnaeus University Dissertations, 198/2014
Keyword
Atrophy, Hypertrophy, Skeletal muscle, Denervation, Protein synthesis, Protein degradation
National Category
Natural Sciences
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-37670 (URN)978-91-87925-26-9 (ISBN)
Public defence
2014-11-21, N2007, Västergård, Smålandsgatan 26E, Kalmar, 09:00 (Swedish)
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Available from: 2014-11-03 Created: 2014-10-15 Last updated: 2015-01-14Bibliographically approved

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Norrby, MarleneEvertsson, KimFjällström, Ann-KristinTågerud, Sven

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