Mutation of mouse Samd4 causes leanness, myopathy, uncoupled mitochondrial respiration, and dysregulated mTORC1 signaling

Zhe Chen, William Holland, John M. Shelton, Aktar Ali, Xiaoming Zhan, Sungyong Won, Wataru Tomisato, Chen Liu, Xiaohong Li, Eva Marie Y Moresco, Bruce Beutler

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Sterile alpha motif domain containing protein 4 (Samd4) is an RNA binding protein that mediates translational repression. We identified a Samd4 missense mutation, designated supermodel, that caused leanness and kyphosis associated with myopathy and adipocyte defects in C57BL/6J mice. The supermodel mutation protected homozygous mice from high fat diet-induced obesity, likely by promoting enhanced energy expenditure through uncoupled mitochondrial respiration. Glucose tolerance was impaired due to diminished insulin release in homozygous mutant mice. The defects of metabolism in supermodel mice may be explained by dysregulated mechanistic target of rapamycin complex 1 (mTORC1) signaling, evidenced by hypophosphorylation of 4E-BP1 and S6 in muscle and adipose tissues of homozygous mice. Samd4 may interface with mTORC1 signaling through an interaction with 14-3-3 proteins and with Akt, which phosphorylates Samd4 in vitro.

Original languageEnglish (US)
Pages (from-to)7367-7372
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number20
DOIs
StatePublished - May 20 2014

ASJC Scopus subject areas

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