In this renewal, we are proposing to extend our studies of mtDNA abnormalities in aging processes. Our efforts have focused on rodent skeletal muscle, demonstrating that age-associated mtDNA deletions accumulate to high levels in a subset of muscle fibers and are associated with ETS abnormal regions of the fibers. These ETS abnormal regions typically lacked complex IV activity (cytochrome c oxidase; some subunits of which are mtDNA-encoded) while being hyperreactive for complex II (succinate dehydrogenase; which is entirely nuclear-encoded). The characterization of ETS abnormal fibers along their length identified regions which dramatically decreased in cross sectional area suggesting an association between deleted mtDNAs, ETS abnormalities, and fiber atrophy. Our objective is to further characterize age-associated ETS abnormal regions and the associated atrophy of skeletal muscle fibers. Since ETS abnormal regions are segmental, these experiments require the characterization of muscle fibers along their length. Five muscles, three of which exhibit age-associated atrophy, will be characterized in F344 x BNF1 rats of various ages (adult to advanced old age). These studies will involve measures of sarcopenia (muscle mass, fiber number and fiber area) combined with histologic analyses of ETS activity and presence of deleted mtDNAs. We will, in addition, address the fate of ETS abnormal fibers through the analysis of fiber area as well as cellular indicators of fiber death (apoptosis and necrosis).

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG011604-04A1
Application #
2765314
Study Section
Special Emphasis Panel (ZRG4-SSS-G (02))
Program Officer
Finkelstein, David B
Project Start
1995-07-10
Project End
2001-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Herbst, Allen; Pak, Jeong W; McKenzie, Debbie et al. (2007) Accumulation of mitochondrial DNA deletion mutations in aged muscle fibers: evidence for a causal role in muscle fiber loss. J Gerontol A Biol Sci Med Sci 62:235-45
Gokey, Nolan G; Cao, Zhengjin; Pak, Jeong W et al. (2004) Molecular analyses of mtDNA deletion mutations in microdissected skeletal muscle fibers from aged rhesus monkeys. Aging Cell 3:319-26
Bua, Entela A; McKiernan, Susan H; Wanagat, Jonathan et al. (2002) Mitochondrial abnormalities are more frequent in muscles undergoing sarcopenia. J Appl Physiol 92:2617-24
Aiken, Judd; Bua, Entela; Cao, Zhengjin et al. (2002) Mitochondrial DNA deletion mutations and sarcopenia. Ann N Y Acad Sci 959:412-23
Cao, Z; Wanagat, J; McKiernan, S H et al. (2001) Mitochondrial DNA deletion mutations are concomitant with ragged red regions of individual, aged muscle fibers: analysis by laser-capture microdissection. Nucleic Acids Res 29:4502-8
Wanagat, J; Cao, Z; Pathare, P et al. (2001) Mitochondrial DNA deletion mutations colocalize with segmental electron transport system abnormalities, muscle fiber atrophy, fiber splitting, and oxidative damage in sarcopenia. FASEB J 15:322-32
Lopez, M E; Van Zeeland, N L; Dahl, D B et al. (2000) Cellular phenotypes of age-associated skeletal muscle mitochondrial abnormalities in rhesus monkeys. Mutat Res 452:123-38
Schwarze, S R; Weindruch, R; Aiken, J M (1998) Oxidative stress and aging reduce COX I RNA and cytochrome oxidase activity in Drosophila. Free Radic Biol Med 25:740-7
Schwarze, S R; Weindruch, R; Aiken, J M (1998) Decreased mitochondrial RNA levels without accumulation of mitochondrial DNA deletions in aging Drosophila melanogaster. Mutat Res 382:99-107

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