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.