Mitochondrial misreading in skeletal muscle accelerates metabolic aging and confers lipid accumulation and increased inflammation

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 Mrps5(V338Y/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.

Automated summary

The experimental model of mitochondrial mistranslation caused by the V338Y amino acid exchange in mitochondrial ribosomal protein MrpS5 has been reported recently. Metabolic profiling of homozygous transgenic Mrps5(V338Y/V338Y) mice revealed enhanced levels of age-related metabolites, increased glycolysis, lipid desaturation, eicosanoid biosynthesis, and alterations of the pentose phosphate pathway. Additionally, transcriptome analysis of aged V338Y mutant muscle showed elevated inflammation, likely due to increased levels of bioactive lipids, indicating age-dependent effects on bioenergetic processes in muscle.