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

The recently discovered aging-dependent large accumulation of point mutatio ns in the human fibroblast mtDNA control region raised the question of thei r occurrence in postmitotic tissues. In the present work, analysis of biops ied or autopsied human skeletal muscle revealed the absence or only minimal presence of those mutations. By contrast, surprisingly, most of 26 individ uals 53 to 92 years old, without a known history of neuromuscular disease, exhibited at mtDNA replication control sites in muscle an accumulation of t wo new point mutations, i.e., A189G and T408A, which were absent or margina lly present in 19 individuals younger than 34 years. These two mutations we re 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). Furth ermore, in several older individuals exhibiting an accumulation in muscle o f 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 h ad accumulated the two muscle-specific point mutations, which were, convers ely, present at only very low levels in four subjects less than or equal to 40 years old. The striking tissue specificity of the muscle mtDNA mutation s detected here and their mapping at critical sites for mtDNA replication s trongly point to the involvement of a specific mutagenic machinery and to t he functional relevance of these mutations.