DIFFERENTIAL OCCURRENCE OF MUTATIONS IN MITOCHONDRIAL-DNA OF HUMAN SKELETAL-MUSCLE DURING AGING

Seven mtDNA mutations (five base substitutions and two deletions) were studied in skeletal muscle samples of 18 human subjects aged 1 hr to 90 years. Quantitative PCR procedures were applied to determine the in cidence (frequency of occurrence) and abundance (percentage of mutant mtDNA out of total mtDNA). The base substitutions, in general, showed a very early onset, three such mutations being detectable in the muscl es of infants aged 1 hr and 5 weeks. Of two disease associated point m utations studied, 3243 A-->G showed significant accumulation with age (P < 0.05), while 8993 T-->G showed no significant age accumulation (P > 0.1). Moreover, three arbitrarily chosen mutations (not disease-ass ociated) showed no age-associated accumulation: two (7029 C-->T and 79 20 A-->G) showed little change over the years (P > 0.1), while the oth er (13167 A-->G) showed a significant decrease (P < 0.05). both the 4, 977-bp and 7,436-bp deletions showed a significant age-associated occu rrence (P < 0.01 and P < 0.05, respectively). The age of onset of dete ctable deletions is about 20-40 years; thereafter, the incidence and a bundance of deletions tend to increase as a function of advancing age. The seven specific mutations were found to occur independent of each other, indicating the random nature of mtDNA mutations in skeletal mus cle. Moreover, the age associated accumulation of multiple deletions w as observed in the same set of muscle tissues, each extract displaying a unique set of multiple PCR products. Thus, mutations in mtDNA occur differentially in human skeletal muscle during aging. (C) 1998 Wiley Liss, Inc.