Date of Award
Doctor of Philosophy (PhD)
Dr. Marie. A. Tamopolsky
Introduction. The mitochondrial theory of aging proposes that a vicious cycle of events including an age-related increase in mitochondrial (mt) reactive oxygen species (ROS) cause damage to mtDNA, resulting in electron transport chain dysfunction (ETC). This, in turn, causes a loss in the ability to maintain cellular energy requirements and results in a further increase in ROS production. Based on several reports of normal ETC activity in skeletal muscle of older adults, there is some question as to whether or not the mitochondrial theory is applicable to skeletal muscle. Resistance exercise (RE) is an efficacious therapy for increasing strength and muscle mass. RE training results in a recovery of strength and muscle fiber cross-sectional area in older adults. As such, resistance exercise should slow or reverse the underlying mechanisms associated with skeletal muscle aging. We conducted a series of experiments to: 1) examine the mitochondrial theory of aging in human skeletal muscle; and 2) examine the effects of RE on variables associated with the mitochondrial theory of aging. We hypothesized that aging would be associated with several aspects of the mitochondrial theory of aging such as an increase in oxidative stress, an alteration in antioxidant capacity, an increase in mtDNA deletions, and a reduction in ETC enzyme activity. Furthermore, we hypothesized that regular RE training would result in an increase in antioxidant enzyme activity, a reduction in oxidative damage to proteins and DNA, and reduction in mtDNA deletions. Methods. Muscle biopsy specimens and urine samples were collected from young and old men, and subsequently analyzed. An initial study examined the effects of aging on mtDNA deletions, oxidative damage to proteins and DNA, antioxidant enzyme activity, and oxidative enzyme activity. Two subsequent studies examined the impact of resistance exercise training on the same variables mentioned above. Results. 1. Oxidative damage to protein and DNA was higher in older vs. younger men. Antioxidant enzyme activity, in particular MnSOD and catalase were higher in old as compared to young. Oxidative enzyme activity was not lower as a function of age. In fact, complex I+III activity was higher in older as compared to younger men. There was a reduction in full-length mtDNA, and the appearance of mtDNA deletions associated with aging. 2. Whole-body RE training for 14 weeks resulted in a decrease in oxidative damage to DNA in older men. Catalase, CuZnSOD, and MnSOD protein content were unchanged, however, mtCK protein content was higher after training. Oxidative enzyme activity was unchanged with the exception of complex N, which demonstrated a specific up-regulation in response to RE training. RE had no effect on full-length mtDNA or mtDNA deletions 3. Unilateral resistance training (12 weeks) had no effect on oxidative damage to protein. Antioxidant enzyme activity, in particular CuZnSOD, and catalase was up-regulated following resistance exercise training. There was no change in oxidative enzyme activity or protein content. Full-length mtDNA was unchanged, and there was no effect of resistance exercise on mtDNA deletions. Conclusion. Aging was associated with an increase in oxidative stress, mtDNA deletions, and significant changes in antioxidant enzymes, suggesting that aspects of the mitochondrial theory of aging were applicable to skeletal muscle. Regular RE training resulted in a decrease in oxidative damage to DNA, and was sufficient to cause a further up-regulation of antioxidant enzyme activity, beyond that induced by aging. Finally, complex IV of the ETC may have indirect antioxidant properties by improving ETC efficiency.
Parise, Gianni, "THE MITOCHONDRIAL THEORY OF AGING IN HUMAN SKELETAL MUSCLE: EFFECTS OF RESISTANCE EXERCISE" (2003). Open Access Dissertations and Theses. Paper 1262.