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Control of protein balance during im...

Krawiec, Brian James.

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Control of protein balance during immobilization-induced skeletal muscle atrophy.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Control of protein balance during immobilization-induced skeletal muscle atrophy./
Author:	Krawiec, Brian James.
Description:	142 p.
Notes:	Source: Dissertation Abstracts International, Volume: 68-05, Section: B, page: 2872.
Contained By:	Dissertation Abstracts International68-05B.
Subject:	Biology, Physiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3266147
ISBN:	9780549048824

Control of protein balance during immobilization-induced skeletal muscle atrophy.
Krawiec, Brian James.

Control of protein balance during immobilization-induced skeletal muscle atrophy. - 142 p.

Source: Dissertation Abstracts International, Volume: 68-05, Section: B, page: 2872.

Thesis (Ph.D.)--The Pennsylvania State University, 2007.

There is a general lack of understanding concerning the changes in protein balance underpinning skeletal muscle wasting. Such knowledge would substantially improve the prognosis and treatment of individuals subject to conditions causing loss of lean body mass. Therefore, the purpose of this thesis was to examine the mechanisms responsible for changes in protein metabolism underlying atrophy using a model of reduced skeletal muscle loading, hindlimb immobilization. Rats were unilaterally casted for up to five days. In the casted limb, gastrocnemius wet weight decreased after three days and thereafter remained constant. Further analysis revealed that this loss of muscle mass was the result of integrated atrophy and growth failure, and demonstrated that there was no defect in the rate of protein synthesis and essential regulators of translation at day five. This muscle atrophy was partially rescued in vivo with a potent proteasome inhibitor and was associated with enhanced mRNA expression of factors that contribute to ubiquitin - proteasome dependent degradation, including the musclespecific ubiquitin ligases MAFbx/Atrogin-1 and MuRF1. The precise means by which the expression of these ubiquitin ligases is controlled is unknown. For this reason, additional investigations using an in vitro model system of skeletal muscle were performed to expand upon the understanding of the cellular signaling events regulating their expression. C2C12 myotubes were treated individually with several AMPK activators, resulting in a dose- and time-dependent modulation of mRNA content of MAFbx/Atrogin-1 and MuRF1 (characterized by an acute repression preceding a sustained induction). These treatments in conjunction with dexamethasone produced a pronounced synergistic effect on ligase mRNA expression at later time points. Stimulation of AMPK activity in vivo via AICAR injection recapitulated the stimulation of MAFbx/Atrogin-1 and MuRF1 expression observed in culture. These data suggest AMPK may be a critical component of the intercalated network of signaling pathways governing skeletal muscle atrophy. In total, the work completed within this thesis has enhanced the understanding of processes fundamental to protein balance (synthesis and degradation) during conditions of skeletal muscle atrophy and identified an additional signaling mechanism which may account for several of the phenotypes displayed by atrophic skeletal muscle.

ISBN: 9780549048824Subjects--Topical Terms:

1017816
Biology, Physiology.

Control of protein balance during immobilization-induced skeletal muscle atrophy.
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100 1 $a Krawiec, Brian James. $3 1267716
245 1 0 $a Control of protein balance during immobilization-induced skeletal muscle atrophy.
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500 $a Source: Dissertation Abstracts International, Volume: 68-05, Section: B, page: 2872.
502 $a Thesis (Ph.D.)--The Pennsylvania State University, 2007.
520 $a There is a general lack of understanding concerning the changes in protein balance underpinning skeletal muscle wasting. Such knowledge would substantially improve the prognosis and treatment of individuals subject to conditions causing loss of lean body mass. Therefore, the purpose of this thesis was to examine the mechanisms responsible for changes in protein metabolism underlying atrophy using a model of reduced skeletal muscle loading, hindlimb immobilization. Rats were unilaterally casted for up to five days. In the casted limb, gastrocnemius wet weight decreased after three days and thereafter remained constant. Further analysis revealed that this loss of muscle mass was the result of integrated atrophy and growth failure, and demonstrated that there was no defect in the rate of protein synthesis and essential regulators of translation at day five. This muscle atrophy was partially rescued in vivo with a potent proteasome inhibitor and was associated with enhanced mRNA expression of factors that contribute to ubiquitin - proteasome dependent degradation, including the musclespecific ubiquitin ligases MAFbx/Atrogin-1 and MuRF1. The precise means by which the expression of these ubiquitin ligases is controlled is unknown. For this reason, additional investigations using an in vitro model system of skeletal muscle were performed to expand upon the understanding of the cellular signaling events regulating their expression. C2C12 myotubes were treated individually with several AMPK activators, resulting in a dose- and time-dependent modulation of mRNA content of MAFbx/Atrogin-1 and MuRF1 (characterized by an acute repression preceding a sustained induction). These treatments in conjunction with dexamethasone produced a pronounced synergistic effect on ligase mRNA expression at later time points. Stimulation of AMPK activity in vivo via AICAR injection recapitulated the stimulation of MAFbx/Atrogin-1 and MuRF1 expression observed in culture. These data suggest AMPK may be a critical component of the intercalated network of signaling pathways governing skeletal muscle atrophy. In total, the work completed within this thesis has enhanced the understanding of processes fundamental to protein balance (synthesis and degradation) during conditions of skeletal muscle atrophy and identified an additional signaling mechanism which may account for several of the phenotypes displayed by atrophic skeletal muscle.
590 $a School code: 0176.
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