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Forkhead box O1 and muscle RING finger 1protein expression in atrophic and hypertrophicdenervated mouse skeletal muscle
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. (Sven Tågerud)
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
2014 (English)In: Journal of Molecular Signaling, ISSN 1750-2187, E-ISSN 1750-2187, Vol. 9, 9Article in journal (Refereed) Published
Abstract [en]

Background: Forkhead box O (FoxO) transcription factors and E3 ubiquitin ligases such as Muscle RING finger 1 (MuRF1) are believed to participate in the regulation of skeletal muscle mass. The function of FoxO transcription factors is regulated by post-translational modifications such as phosphorylation and acetylation. In the present study FoxO1 protein expression, phosphorylation and acetylation as well as MuRF1 protein expression, were examined in atrophic and hypertrophic denervated skeletal muscle. Methods: Protein expression, phosphorylation and acetylation were studied semi-quantitatively using Western blots. Muscles studied were 6-days denervated mouse hind-limb muscles (anterior tibial as well as pooled gastrocnemius and soleus muscles, all atrophic), 6-days denervated mouse hemidiaphragm muscles (hypertrophic) and innervated control muscles. Total muscle homogenates were used as well as separated nuclear and cytosolic fractions of innervated and 6-days denervated anterior tibial and hemidiaphragm muscles. Results: Expression of FoxO1 and MuRF1 proteins increased 0.3-3.7-fold in all 6-days denervated muscles studied, atrophic as well as hypertrophic. Phosphorylation of FoxO1 at S256 increased about 0.8-1-fold after denervation in pooled gastrocnemius and soleus muscles and in hemidiaphragm but not in unfractionated anterior tibial muscle. A small (0.2-fold) but statistically significant increase in FoxO1 phosphorylation was, however, observed in cytosolic fractions of denervated anterior tibial muscle. A statistically significant increase in FoxO1 acetylation (0.8-fold) was observed only in denervated anterior tibial muscle. Increases in total FoxO1 and in phosphorylated FoxO1 were only seen in cytosolic fractions of denervated atrophic anterior tibial muscle whereas in denervated hypertrophic hemidiaphragm both total FoxO1 and phosphorylated FoxO1 increased in cytosolic as well as in nuclear fractions. MuRF1 protein expression increased in cytosolic as well as in nuclear fractions of both denervated atrophic anterior tibial muscle and denervated hypertrophic hemidiaphragm muscle. Conclusions: Increased expression of FoxO1 and MuRF1 in denervated muscles (atrophic as well as hypertrophic) suggests that these proteins participate in the tissue remodelling occurring after denervation. The effect of denervation on the level of phosphorylated and acetylated FoxO1 differed in the muscles studied and may be related to differences in fiber type composition of the muscles.

Place, publisher, year, edition, pages
BioMed Central, 2014. Vol. 9, 9
Keyword [en]
Acetylation, Atrophy, Denervation, Cytosolic fraction, Forkhead box O, Hypertrophy, MuRF1, Nuclear fraction, Phosphorylation, Skeletal muscle
National Category
Biochemistry and Molecular Biology
Research subject
Natural Science, Biomedical Sciences
Identifiers
URN: urn:nbn:se:lnu:diva-37669DOI: 10.1186/1750-2187-9-9Scopus ID: 2-s2.0-84907392088OAI: oai:DiVA.org:lnu-37669DiVA: diva2:755880
Available from: 2014-10-15 Created: 2014-10-15 Last updated: 2016-11-29Bibliographically 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)
Opponent
Supervisors
Available from: 2014-11-03 Created: 2014-10-15 Last updated: 2015-01-14Bibliographically approved

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Fjällström, Ann-KristinEvertsson, KimNorrby, MarleneTågerud, Sven
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