DESCRIPTION Fifteen to 30% of stroke survivors are permanently disabled, which usually leads to a sedentary lifestyle and functional dependence following stroke. While it is known that hemiparetic gait elevates the energy cost of ambulatory activity by 1.5- 2 fold, how chronic stroke affects total daily energy expenditure (TDEE) and dietary intake is currently unknown. Altered energy balance (expenditure ` intake) may result in impaired substrate oxidation and skeletal muscle oxidative stress. Elevated oxidative stress in skeletal muscle is associated with fatigue and decreased cardiovascular and muscular endurance. Treadmill exercise training in older, non-stroke populations improves home ambulatory activity, physical function, and metabolic profiles and has antioxidant effects in skeletal muscle. Additionally, ensuring that energy and macronutrient intake meets an individual's energy and fuel needs may result in decreases in oxidative damage. This randomized control study tests the hypothesis that treadmill rehabilitation plus nutritional modification ("heart healthy" diet plus adequate protein) (TM+N) versus stretching plus nutritional modification (ST+N) (nutrition control) will 1) improve energy balance and substrate oxidation, 2) reduce systemic and tissue level oxidative stress, and 3) that the respective comparison of these interventions (TM+N and ST+N) to treadmill (TM) and stretching (ST) controls from her mentor's current R01 will support the rehabilitative role of nutritional modification in stroke. We propose the following aims: Aim 1: To assess the effects of six months of TM+N versus ST+N on TDEE and substrate oxidation in chronic stroke survivors. Aim 2: To examine the effects of six months of TM+N versus ST+N on systemic and tissue oxidative stress and antioxidant capacity in chronic stroke survivors. Aim 3: To compare the effects of TM+N and ST+N versus TM and ST alone, respectively, on energy balance and systemic and tissue oxidative stress, in chronic stroke survivors. Older (55-75 years), men and postmenopausal women (n=50) with chronic stroke (at least 6 months post stroke) with stable neurological deficits will be recruited. Subjects will be randomized to participate in six months o dietary modification (<30% of calories as fat, <10% as saturated fat, <2,400 mg sodium, 25 g/d of fiber, and 1.0-1.2 g/kg/d of lean protein) plus aerobic exercise training or dietary modificatio plus whole body stretching. Seven-day accelerometry and dietary records will be used to determine energy balance. Indirect calorimetry will be used to determine substrate oxidation during fasting and a peak and submaximal exercise bout. Blood draws and paretic and non-paretic vastus lateralis skeletal muscle biopsies will be performed to determine changes in systemic and tissue level oxidative stress content (nitrate/nitrite and thiobarbituric acid reactiv substances) and antioxidant capacity (superoxide dismutase, glutathione peroxidase, and catalase) following exercise rehabilitation or stretching with and without nutritional modification in chronic stroke survivors. The mentoring and training described in this CDA-2 application will greatly enhance the nominee's development into an independent investigator, while simultaneously identifying mechanisms by which aerobic exercise rehabilitation with nutritional modification can improve TDEE and reduce oxidative stress. We postulate that this study will provide evidence to improve stroke treatment, substrate utilization, and the antioxidant capacity of blood and skeletal muscle and reduce physical inactivity in Veteran stroke survivors, potentially leading to a reduction in clinical costs related to the care of Veterans with disabilit from chronic stroke.

The research in this VA CDA-2 application will examine the effects of exercise rehabilitation with nutritional modification on total daily energy expenditure and substrate utilization in older Veteran stroke survivors. Further, it will determine mechanisms by which exercise training with nutritional modification may alter oxidative stress in older Veteran stroke survivors. This is especially relevant to Veterans' health, as physical inactivity, chronic disability, and inadequate dietary intake are highly prevalent among older Veterans and risk factors for recurrent stroke. Currently, treatment of stroke results in substantial VA health care costs. The identification of rehabilitation methods which improve energy balance, while reducing oxidative stress would have a significant impact on Veteran stroke survivors, and potentially lead to a reduction in pharmaceutical and clinical costs related to the care of Veterans with disability from chronic stroke.