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Final dissertation pdf June 19 2014.pdf (1019.71 KB)
ETD Abstract Container
Abstract Header
The Impact of FoxO1 on Skeletal Muscle Protein Synthesis
Author Info
Potter, Rachael Ann
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1403208596
Abstract Details
Year and Degree
2014, Doctor of Philosophy, University of Toledo, Exercise Science.
Abstract
The regulation of skeletal muscle is dependent upon the balance between protein synthesis and protein degradation. The FoxO1 transcription factor engages in an important role in regulating skeletal muscle hypertrophy through upregulation of atrophy related genes (i.e. MAFbx/atrogin-1). Studies have shown that FoxO1 regulates skeletal muscle atrophy through both apoptotic and proteolytic pathways in various tissues. However, the interaction between FoxO1 overexpression and protein synthesis is unknown. The hypotheses tested include: i) the overexpression of FoxO1 in vitro suppresses skeletal muscle protein synthesis and ii) suppression of skeletal muscle protein synthesis is due to suppression of ribosome biogenesis. An in vitro model was used in which FoxO1 estrogen receptor fusion proteins were transfected into skeletal muscle myoblasts and grown into myotubes. The differentiated myotubes were treated with 4-hydroxytamoxifen (4-OHT) to activate the FoxO1 estrogen receptor fusion proteins and with insulin as a hypertrophic stimulus for 30 minutes, 60 minutes, and 120 minutes. The cells were treated with [3H] phenylalanine to measure total protein synthesis upon FoxO1 overexpression. In addition, expression of key anabolic molecules including Akt, p70s6k, ribosomal protein S6, and Cyclin D1 activity was assessed via western blot. Our findings show that i) FoxO1 overexpression significantly suppresses protein synthesis in differentiated myotubes, ii) despite treatment with insulin; FoxO1 overexpression blunts protein synthesis compared to control myotubes, iii) FoxO1 overexpression suppresses activation of Akt and ribosomal protein S6. In addition, insulin treatment did not elevate phosphorylation of ribosomal protein S6 upon FoxO1 overexpression. In this study, the major finding is that FoxO1 overexpression suppresses protein synthesis prior to any phenotypic loss of protein content in a ribosomal protein S6 dependent manner. In addition, total protein synthesis is suppressed despite treatment with insulin. Therefore, decreased skeletal muscle size is attributed to both increased protein degradation and suppression of protein synthesis. It can be speculated that the suppression of protein synthesis is due, at least in part, to alterations in ribosomal biogenesis. Future direction will focus on ribosomal biogenesis to elucidate the mechanism to which FoxO1 suppresses protein synthesis.
Committee
Thomas McLoughlin, Ph.D. (Committee Chair)
Francis Pizza, Ph.D. (Committee Member)
Joseph Marino, Ph.D. (Committee Member)
Abraham Lee, Ph.D. (Committee Member)
Pages
66 p.
Subject Headings
Biology
;
Kinesiology
;
Physiology
Keywords
FoxO1
;
Skeletal Muscle Atrophy
;
Protein Synthesis
;
Muscle Physiology
Recommended Citations
Refworks
EndNote
RIS
Mendeley
Citations
Potter, R. A. (2014).
The Impact of FoxO1 on Skeletal Muscle Protein Synthesis
[Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1403208596
APA Style (7th edition)
Potter, Rachael.
The Impact of FoxO1 on Skeletal Muscle Protein Synthesis.
2014. University of Toledo, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1403208596.
MLA Style (8th edition)
Potter, Rachael. "The Impact of FoxO1 on Skeletal Muscle Protein Synthesis." Doctoral dissertation, University of Toledo, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1403208596
Chicago Manual of Style (17th edition)
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Document number:
toledo1403208596
Download Count:
522
Copyright Info
© 2014, all rights reserved.
This open access ETD is published by University of Toledo and OhioLINK.