Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication.
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 < or =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.
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Y
Y
Wang
Y
Y
Michikawa
C
C
Mallidis
Y
Y
Bai
L
L
Woodhouse
K E
KE
Yarasheski
C A
CA
Miller
V
V
Askanas
W K
WK
Engel
S
S
Bhasin
G
G
Attardi
D000328:Adult; D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009132:Muscles / Q000502:physiology*; D017354:Point Mutation
D004272:DNA, Mitochondrial