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

Area of Science:

• Mitochondrial biology
• Molecular genetics
• Metabolomics

Background:

• Mitochondrial protein synthesis is crucial for cellular energy production.
• Mitochondrial mistranslation, errors in protein synthesis within mitochondria, can disrupt function.
• An experimental model of mitochondrial mistranslation was previously established using the MrpS5V338Y mutation.

Purpose of the Study:

• To investigate the consequences of mitochondrial mistranslation in skeletal muscle.
• To analyze age-dependent changes in metabolism and gene expression in MrpS5V338Y/V338Y mice.
• To understand the link between mitochondrial dysfunction and age-associated pathologies.

Main Methods:

• RNA-sequencing (RNA-Seq) to analyze gene expression profiles.
• Metabolic profiling to assess biochemical changes in tissues.
• Comparative analysis between homozygous transgenic MrpS5V338Y/V338Y mice and wild-type controls.
• Focus on post-mitotic skeletal muscle tissue.

Main Results:

• Homozygous MrpS5V338Y/V338Y mice exhibited age-dependent metabolic alterations in skeletal muscle.
• Increased levels of age-associated metabolites, enhanced glycolysis, lipid desaturation, and eicosanoid biosynthesis were observed.
• Alterations in the pentose phosphate pathway and elevated inflammation signatures in aged mutant muscle were detected.
• These changes are likely linked to increased bioactive lipids and chronic mitochondrial dysfunction.

Conclusions:

• Mitochondrial mistranslation impairs specific bioenergetic processes in skeletal muscle.
• The effects of mitochondrial dysfunction are age-dependent and manifest in metabolic and inflammatory pathways.
• The MrpS5V338Y mouse model provides insights into age-related muscle decline and mitochondrial disease mechanisms.