ROLE OF THE MAMMALIAN TARGET OF RAPAMYCIN IN THE REGULATION OF SKELETAL MUSCLE PROTEIN SYNTHESIS AND eIF2B EPSILON mRNA TRANSLATION FOLLOWING ACUTE RESISTANCE EXERCISE

Open Access
- Author:
- Kubica, Neil
- Graduate Program:
- Physiology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- July 20, 2005
- Committee Members:
- Leonard Shelton Jefferson Jr., Committee Chair/Co-Chair
Peter A Farrell, Committee Member
Scot R Kimball, Committee Member
Charles H Lang, Committee Member
Charles D Smith, Committee Member - Keywords:
- eIF2B
mTOR
PKB
mRNA translation
skeletal muscle - Abstract:
- Understanding the molecular basis of skeletal muscle protein synthesis and hypertrophy is critical to the development of targets for therapeutic intervention in muscle wasting conditions. There has recently been a great deal of investigation regarding the action of protein kinase B (PKB) and the mammalian target of rapamycin (mTOR) in the regulation of mRNA translation initiation and subsequent global rates of protein synthesis following muscle contractions or resistance exercise. Previous work has also suggested that the activity of the rate-limiting eukaryotic initiation factor 2B (eIF2B) is elevated concomitant with increases in protein synthesis following an acute bout of resistance exercise. The mechanisms regulating eIF2B activity following exercise are explored in the present dissertation, with an emphasis on potential interaction between PKB/mTOR signaling and eIF2B activity. It is demonstrated herein, that: 1) abundance of mRNAs encoding eIF2B subunits are increased late in the recovery period following an acute bout of resistance exercise, following the time period associated with an increase in protein synthetic rates, 2) PKB/mTOR signaling is rapidly, but transiently induced within the first hour following exercise prior to any observed increase in protein synthesis, 3) signaling through mTOR is required for increased muscle protein synthesis and efficient initiation of mRNA translation following exercise, and 4) eIF2B? mRNA translation/protein expression is increased in a mTOR-dependent manner concomitant with elevated rates of protein synthesis. In the context of previous work in the currently employed model of resistance exercise, these findings suggested that early activation of mTOR following exercise may result in translation control of pro-growth mRNAs, such as eIF2B?, that contribute to increased rates of protein synthesis later in the recovery time course. The novel role for mTOR in the regulation of eIF2B? mRNA translation may be a general mechanism for control of global rates of protein synthesis, as this result is also observed in response to leucine and IGF-1 in Rat 2 fibroblasts.