MITOCHONDRIAL DNA DELETION MUTATIONS AND SARCOPENIA
Judd Aiken
Dept. Animal Health & Biomedical Sciences, 1656 Linden Dr. University of
Wisconsin, Madison, Wisconsin 53706
Mitochondrial DNA (mtDNA) deletion mutations accumulate with age and
have been shown by in situ hybridization studies to be present in
regions of muscle fibers exhibiting electron transport system (ETS)
abnormalities. To further investigate the link between mtDNA deletion
mutations and fiber loss, skeletal muscle from Fisher 344X Brown Norway
F1 hybrid rats and from rhesus monkeys of diverse ages were
histologically characterized for mitochondrial DNA and enzymatic
abnormalities. Serial, transverse cryomicrotome sections, spanning a
1,000 micron region of muscle, were obtained for histologic analyses.
In situ histochemical staining for succinate dehydrogenase (SDH) and
cytochrome c oxidase (COX) activity was performed. The successive
sections were analyzed for the presence of fibers displaying ETS
abnormal phenotypes, including negative staining for COX and
hyperreactive staining for SDH. In quadriceps muscles of both rat and
rhesus monkeys, there is an age-associated decline in fiber number.
The number of ETS abnormal fibers increased with age.
Through the measurement of cross-sectional area of ETS abnormal fibers
throughout the length of the fiber, both within the ETS abnormal region
and in the phenotypically normal region, an intrafiber atrophy and/or
fiber breakage specifically associated with the ETS abnormal region was
identified. Laser capture microdissection was used to isolate sections
of ETS abnormal fibers for PCR-based analysis of mtDNA deletions. All
ETS abnormal fibers examined contained deleted mitochondrial genomes.
MtDNA deletion mutations, therefore, accumulate with age and are
distributed within skeletal muscle fibers mosaically and segmentally
(i.e. deletions accumulate in a subset of fibers within a small region
of the affected fiber). These studies demonstrate that mitochondrial
DNA (mtDNA) deletions are linked to fiber atrophy and fiber loss and
suggest a causal role of age-associated mtDNA mutations in sarcopenia.
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