The role of mtDNA deletion mutations in sarcopenia
J.M. Aiken, D. McKenzie
University of Wisconsin at Madison, 1656 Linden Dr., Madison, WI 53706, USA
Considerable muscle fiber loss occurs in quadriceps muscles of mammals
with age. Our studies indicate that the molecular basis of this fiber
loss is the accumulation of mtDNA deletion mutations within a muscle
fiber to levels that result in mitochondrial electron transport system
(ETS) abnormalities, intra-fiber atrophy, fiber breakage and fiber
loss. If mtDNA deletion mutations play a role in muscle fiber loss
with age, a number of testable hypotheses would have to be valid.
These include: i) mtDNA mutations accumulate to high levels
intracellularly, ii) the concomitant presence of abnormal ETS
phenotype(s) with deletion mutations, iii) the accumulation of muscle
fibers exhibiting high levels of mtDNA deletion mutations and ETS
abnormalities, iv) the accumulation of mitochondrial abnormalities
should be temporally concomitant with muscle fiber loss and v) fewer
mitochondrial abnormalities in muscles from aged calorically restricted
(an intervention that maintains fiber number with age) animals compared
to age-matched controls.
To test these hypotheses, we have examined rodents and monkeys from
middle to extreme old age. Our studies demonstrate that mtDNA deletion
mutations and the mitochondrial enzymatic abnormalities they trigger
accumulate to high levels, this accumulation occurs temporally with
muscle fiber loss and that CR reduces the number of ETS abnormalities.
Key words:
mtDNA, sarcopenia, muscle, calorie restriction, ETS abnormalities
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