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

Proc Natl Acad Sci U S A. 2014 May 20;111(20):7367-72. doi: 10.1073/pnas.1406511111. Epub 2014 May 5.

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.

Keywords: Akt/PKB; N-ethyl-N-nitrosourea.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 14-3-3 Proteins / metabolism
  • Adipocytes / cytology
  • Amino Acid Motifs
  • Animals
  • Body Composition
  • Female
  • Glucose / metabolism
  • Glucose Tolerance Test
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Inbred C57BL
  • Multiprotein Complexes / metabolism*
  • Mutagenesis
  • Mutation*
  • Phenotype
  • Phosphorylation
  • RNA-Binding Proteins / metabolism
  • Repressor Proteins / genetics*
  • Repressor Proteins / physiology
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • 14-3-3 Proteins
  • Multiprotein Complexes
  • RNA-Binding Proteins
  • Repressor Proteins
  • Smaug1 protein, mouse
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Glucose