Selective Accumulation of mtDNA Deletion Mutations in Aged Skeletal Muscle





J.W. Pak, J.M. Aiken

Department of Animal Health and Biomedical Sciences, University of Wisconsin, 1656 Linden Dr., Madison, WI 53706, USA



MtDNA deletion mutations accumulate to high levels in aged muscle fibers. This accumulation is segmental and focal; i.e., only a portion of a fiber is affected by each deletion event. Concomitant with the deletion mutations are enzyme abnormalities of the electron transport system (ETS) and intra-fiber atrophy. Quantitation of the deletion mutation abundance within ETS dysfunctional region demonstrated that greater than 90% of the mitochondrial genomes contained deletion mutations. MtDNA deletion mutations accumulate to levels resulting in phenotypic changes only in muscles that undergo sarcopenia. For example, high levels of deletion mutations and ETS abnormal fibers are present in aged vastus lateralis muscle but are very rare in soleus.

In this study, we compared the mtDNA deletion mutations in ETS normal and abnormal fibers from vastus lateralis, rectus femoris and soleus. We found mtDNA deletion mutations in the soleus of young animals and the frequency of deletion events appears to increase with age. Quantitation of deletion events in soleus, however, demonstrates that these mutations do not accumulate intracellularly to high levels and are not linked to the ETS abnormal phenotype. There are also significant differences in the deletion size and in the distribution of deletion breakpoints between ETS normal and ETS abnormal fibers indicating that the generation of deletion mutations is a separate event from replication and accumulation of the deleted genomes. These results suggest that accumulation of a deletion mutation to levels responsible for age-related phenotypes is regulated by multiple factors including location of breakpoints, deletion size, muscle function and fiber type.




Key words: Mitochondrial DNA, deletion mutations, ETS abnormality, fiber type, sarcopenia







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