All ETDs from UAB

Advisory Committee Chair

Marcas Bamman

Advisory Committee Members

Tim Garvey

Tim Nagy

Stuart Frank

Edward Blalock

Paul Goepfert

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The regulation of protein synthesis (i.e., mRNA translation) is an energetically costly and extensively regulated process, which is primarily regulated at the initiation step. Mechanical load is a potent stimulus of translation in skeletal muscle, and thus this tissue provides an excellent model system to study the plasticity of the translational apparatus. We investigated the effects of alterations in translation initiation cell signaling pathways in skeletal muscle using a variety of in vitro and in vivo mouse and human model systems. Collectively, our results suggest that, although many proteins in translational signaling pathways are responsive to mechanical load, the response of most were congruent with neither direct measures of muscle protein synthesis rates nor the degree of mechanical load-induced myofiber hypertrophy in humans. Of 11 translational signaling components examined, only p70S6K (T421/S424) phosphorylation and eIF2Bε abundance after acute mechanical loading were associated with eventual myofiber hypertrophy. Subsequent studies therefore focused on these two proteins. We found that overexpression of eIF2Bε was sufficient to increase cap-dependent protein synthesis rates in myogenic cells in vitro. Expression of eIF2Bε in mouse skeletal muscle in vivo was sufficient to increase myofiber size after only seven days. Although there was an in vivo association between p70S6K signaling and eIF2Bε bundance, genetic alteration of p70S6K signaling was not sufficient to increase eIF2Bε abundance in multiple cell lines in vitro or in mouse skeletal muscle in vivo. Overall, this series of experiments demonstrates, for the first time, that eIF2Bε is an important determinant of myofiber size, and that augmentation of eIF2Bε abundance may largely dictate the degree of load-induced myofiber hypertrophy. These studies provide mechanistic insight into eIF2Bε-dependent regulation of myogenic cell size, which likely has important implications for cell size determination in all mammalian cells.

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