Random errors in protein synthesis activate an age-dependent program of muscle atrophy in mice

Autor: David P. Wolfer, Dimitri Shcherbakov, Anne Eckert, Martina Nigri, Kader Thiam, James M. Moore, Rashid Akbergenov, Patricia Isnard-Petit, Stephan Frank, Amandine Grimm, Lisa Michelle Restelli, Petra Seebeck, Erik C. Böttger
Přispěvatelé: University of Zurich, Böttger, Erik C
Rok vydání: 2021
Předmět:
Male
0301 basic medicine
Genetically modified mouse
Aging
10017 Institute of Anatomy
QH301-705.5
Medicine (miscellaneous)
610 Medicine & health
1100 General Agricultural and Biological Sciences
Biology
medicine.disease_cause
Article
General Biochemistry
Genetics and Molecular Biology

Mice
03 medical and health sciences
0302 clinical medicine
1300 General Biochemistry
Genetics and Molecular Biology

medicine
Animals
Biology (General)
Transcriptomics
PI3K/AKT/mTOR pathway
Mutation
10179 Institute of Medical Microbiology
Skeletal muscle
2701 Medicine (miscellaneous)
Translation (biology)
Ribosome
Phenotype
Muscle atrophy
Protein quality control
Cell biology
Mice
Inbred C57BL

Muscular Atrophy
030104 developmental biology
medicine.anatomical_structure
Protein Biosynthesis
FOXO3
570 Life sciences
biology
Female
medicine.symptom
Transcriptome
General Agricultural and Biological Sciences
Ribosomes
030217 neurology & neurosurgery
Zdroj: Communications Biology, Vol 4, Iss 1, Pp 1-11 (2021)
Communications Biology, 4 (1)
Communications Biology
ISSN: 2399-3642
DOI: 10.1038/s42003-021-02204-z
Popis: Random errors in protein synthesis are prevalent and ubiquitous, yet their effect on organismal health has remained enigmatic for over five decades. Here, we studied whether mice carrying the ribosomal ambiguity (ram) mutation Rps2-A226Y, recently shown to increase the inborn error rate of mammalian translation, if at all viable, present any specific, possibly aging-related, phenotype. We introduced Rps2-A226Y using a Cre/loxP strategy. Resulting transgenic mice were mosaic and showed a muscle-related phenotype with reduced grip strength. Analysis of gene expression in skeletal muscle using RNA-Seq revealed transcriptomic changes occurring in an age-dependent manner, involving an interplay of PGC1α, FOXO3, mTOR, and glucocorticoids as key signaling pathways, and finally resulting in activation of a muscle atrophy program. Our results highlight the relevance of translation accuracy, and show how disturbances thereof may contribute to age-related pathologies.
Communications Biology, 4 (1)
ISSN:2399-3642
Databáze: OpenAIRE