Semester

Fall

Date of Graduation

2010

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Stephen E. Alway.

Abstract

Resveratrol (3,5,4,trihydroxystilbene) is a naturally occurring polyphenol found in over seventy plant species that has been shown to have anti-oxidant, anti-apoptotic and anti-aging properties. Resveratrols' capacity to enhance the endogenous anti-oxidant system, upregulate anti-apoptotic proteins and improve mitochondrial function, presumably through the activation of the N AD+ dependent deacetylase Sirtuin1, suggests that supplementation with resveratrol may potentially protect skeletal muscle from the detrimental effects of increases in oxidative stress and the subsequent increase in apoptotic signaling that are present in many atrophic conditions. Therefore, the major goals of this dissertation are to further understand the interplay between oxidative stress and skeletal muscle atrophy and to evaluate the efficacy of resveratrol as a counter measure to both mitochondrial-induced oxidative stress and apoptosis.;The first study used hindlimb suspension (HLS) as a model of disuse atrophy as it is known to elicit muscle atrophy, oxidative stress and apoptosis in skeletal muscle. The aim of the investigation was to analyze the capacity of resveratrol administration at a moderate dose of 12.5mg/kg/day for 21 days to attenuate oxidative stress, apoptosis and muscle force loss following 14 days of HLS in young and aged rats. The study yielded mixed results. Resveratrol administration effectively reduced oxidative stress and subsequently oxidative damage in muscles from aged animals. Furthermore, resveratrol administration attenuated the relative loss of muscle mass as a ratio of animal body weight in gastrocnemius muscles from aged animals; however, despite reductions in apoptotic signaling in aged muscles, resveratrol administration was unable to mitigate apoptosis as measured by DNA fragmentation. Moreover, resveratrol administration had no protective effect on gastrocnemius muscles from young animals with regard to oxidative or apoptotic indices. Based on these results resveratrol has the potential to be an effective therapeutic agent to treat muscle functional decrements associated with disuse in aged individuals, via improving the redox status associated with these conditions.;The second half of the dissertation focuses on the capacity of long-term dietary supplementation with resveratrol to protect against aging-induced oxidative stress and to enhance mitochondrial signaling, and thus stem the progression of sarcopenia in aged skeletal muscle. In this study middle-aged (18mo) C57BL/6 mice were supplemented with a diet containing .05% trans-resveratrol for 10 months until they reached senescence (28mo). Gastrocnemius, plantaris and vastus lateralis muscles from supplemented animals were compared for anti-oxidant enzyme content and activities, oxidant load, oxidative damage, mitochondrial integrity and mass, as well as muscle function indices with muscles from young and middle-aged animals receiving a control diet. Resveratrol specifically upregulated the capacity of the mitochondrial isoform of superoxide dismutase (MnSOD) and concomitantly decreased hydrogen peroxide concentrations. This was paralleled by reductions in lipid peroxidation, but not protein oxidation in muscles from supplemented animals. Despite reductions in oxidant load and lipid peroxidation resveratrol, supplementation was unable to confer protection against sarcopenia. Furthermore, plantaris muscles from supplemented aged animals did not show enhanced resistance to muscle fatigue, nor an increase in maximal force production.;Taken as a whole these results suggest that resveratrol may be most effective when used as a pharmacological pre-conditioner to help confer resistance to oxidative damage under perturbations that are known to increase oxidative stress. Specifically, resveratrol may be an effective therapeutic agent to improve the redox status of aged skeletal muscle and therefore allow for improved adaptation and recovery following chronic illness and/or injuries during which the capacity of the endogenous antioxidant system may be overwhelmed in aged individuals. Gaining clearer insight into the molecular signaling pathways involved in aging and disuse muscle atrophy is paramount in developing nutritional and/or pharmacological interventions to minimize protein loss and attenuate the functional decrements associated with atrophic conditions. (Abstract shortened by UMI.).

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