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Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication

Wang, Yan and Michikawa, Yuichi and Mallidis, Con and Bai, Yan and Woodhouse, Linda and Yarasheski, Kevin E. and Miller, Carol A. and Askanas, Valerie and Engel, W. King and Bhasin, Shalender and Attardi, Giuseppe (2001) Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication. Proceedings of the National Academy of Sciences of the United States of America, 98 (7). pp. 4022-4027. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:WANpnas01

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Abstract

The recently discovered aging-dependent large accumulation of point mutations in the human fibroblast mtDNA control region raised the question of their occurrence in postmitotic tissues. In the present work, analysis of biopsied or autopsied human skeletal muscle revealed the absence or only minimal presence of those mutations. By contrast, surprisingly, most of 26 individuals 53 to 92 years old, without a known history of neuromuscular disease, exhibited at mtDNA replication control sites in muscle an accumulation of two new point mutations, i.e., A189G and T408A, which were absent or marginally present in 19 individuals younger than 34 years. These two mutations were not found in fibroblasts from 22 subjects 64 to 101 years of age (T408A), or were present only in three subjects in very low amounts (A189G). Furthermore, in several older individuals exhibiting an accumulation in muscle of one or both of these mutations, they were nearly absent in other tissues, whereas the most frequent fibroblast-specific mutation (T414G) was present in skin, but not in muscle. Among eight additional individuals exhibiting partial denervation of their biopsied muscle, four subjects >80 years old had accumulated the two muscle-specific point mutations, which were, conversely, present at only very low levels in four subjects ≤40 years old. The striking tissue specificity of the muscle mtDNA mutations detected here and their mapping at critical sites for mtDNA replication strongly point to the involvement of a specific mutagenic machinery and to the functional relevance of these mutations.


Item Type:Article
Additional Information:© 2001 by the National Academy of Sciences. Contributed by Giuseppe Attardi, January 5, 2001. We thank Drs. A. Chomyn and T. Suzuki for valuable discussions, and B. Keeley and L. Bellavia for expert technical assistance. This work was supported by National Institute on Aging [National Institutes of Health (NIH)] Grant AG12117 (to G.A.); and by NIH Grant 1R01AG14369, Research Centers in Minority Institutions (RCMI) Clinical Research Initiative (P20RR11145), and RCMI Grants G12RR03026 and U54RR14616 (to S.B.). Y.W. and Y.M. contributed equally to this work. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Subject Keywords:HUMAN MITOCHONDRIAL-DNA; CONTROL REGION; SEQUENCE; CELL; ORIGIN; TRANSCRIPTION; GENOME; AGE
Record Number:CaltechAUTHORS:WANpnas01
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:WANpnas01
Alternative URL:http://dx.doi.org/10.1073/pnas.061013598
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:10540
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:15 May 2008
Last Modified:26 Dec 2012 10:01

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