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Adaptations to chronic rapamycin in mice.

Sherry G Dodds1, Carolina B Livi1,2, Manish Parihar1

  • 1Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center San Antonio, San Antonio, TX, USA.

Pathobiology of Aging & Age Related Diseases
|May 31, 2016
PubMed
Summary

Chronic encapsulated rapamycin (eRapa) extends lifespan but has complex effects on cells. In mouse colon, eRapa unexpectedly increased ribosome biogenesis and translation, creating a pseudo-anabolic state, unlike in fat tissue.

Keywords:
mTORC1rapamycinribosome biogenesistranslation

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Area of Science:

  • Cellular and Molecular Biology
  • Aging Research
  • Pharmacology

Background:

  • Rapamycin inhibits mTOR, a key regulator of protein synthesis.
  • Chronic rapamycin treatment extends lifespan in mice.
  • Long-term organ-level effects of rapamycin are not fully understood.

Purpose of the Study:

  • To investigate the long-term effects of encapsulated rapamycin (eRapa) on mTORC1 signaling and ribosome biogenesis (RiBi) in mouse colon and visceral adipose tissue.
  • To determine if chronic eRapa treatment leads to decreased protein production at the organ level.

Main Methods:

  • Mice were chronically treated with encapsulated rapamycin (eRapa).
  • mTORC1 signaling was assessed by measuring phosphorylated S6K substrate, rpS6.
  • Ribosome biogenesis (RiBi) was evaluated by quantifying 18S rRNA and ribosomal protein gene expression (RPGs).
  • Translation initiation factors eIF4E and 4E-BP1 levels were measured.

Main Results:

  • Chronic eRapa decreased phosphorylated rpS6 in both colon and fat, confirming mTORC1 inhibition.
  • Unexpectedly, colon tissue showed increased 18S rRNA and RPGs, indicating enhanced RiBi and a 'pseudo-anabolic' state.
  • Colon tissue also exhibited increased eIF4E relative to 4E-BP1, suggesting enhanced translation.
  • Visceral adipose tissue showed opposite trends for 18S rRNA and differential regulation of specific RPGs and translation factors compared to colon.

Conclusions:

  • Chronic eRapa treatment induces distinct, tissue-specific adaptive responses.
  • The colon exhibits an adaptive 'pseudo-anabolic' state with increased RiBi and translation, contrasting with cell-based predictions.
  • Fat tissue shows a different response pattern, possibly due to varying rapamycin levels, cell types, or genetic background.