Mitochondrial misreading in skeletal muscle accelerates metabolic aging and confers lipid accumulation and increased inflammation
- Dimitri Shcherbakov1,4,
- Stefan Duscha1,4,
- Reda Juskeviciene1,
- Lisa M. Restelli2,
- Stephan Frank2,
- Endre Laczko3 and
- Erik C. Böttger1
- 1Institut für Medizinische Mikrobiologie, Universität Zürich, 8006 Zürich, Switzerland
- 2Division of Neuropathology, Institute of Medical Genetics and Pathology, Basel University Hospital, 4031 Basel, Switzerland
- 3Functional Genomics Center Zurich, ETH Zürich und Universität Zürich, 8057 Zürich, Switzerland
- Corresponding author: boettger{at}imm.uzh.ch
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↵4 These authors contributed equally to this work.
Abstract
We have recently reported on an experimental model of mitochondrial mistranslation conferred by amino acid exchange V338Y in mitochondrial ribosomal protein MrpS5. Here we used a combination of RNA-seq and metabolic profiling of homozygous transgenic Mrps5V338Y/V338Y mice to analyze the changes associated with the V338Y mutation in postmitotic skeletal muscle. Metabolome analysis demonstrated enhanced levels of age-associated metabolites in the mutant V338Y animals accompanied by increased glycolysis, lipid desaturation and eicosanoid biosynthesis, and alterations of the pentose phosphate pathway. In addition, transcriptome signatures of aged V338Y mutant muscle pointed to elevated inflammation, likely reflecting the increased levels of bioactive lipids. Our findings indicate that mistranslation-mediated impairment of mitochondrial function affects specific bioenergetic processes in muscle in an age-dependent manner.
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Footnotes
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Article is online at http://www.rnajournal.org/cgi/doi/10.1261/rna.077347.120.
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Freely available online through the RNA Open Access option.
- Received July 20, 2020.
- Accepted November 23, 2020.
This article, published in RNA, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.