DESCRIPTION (provided by applicant): Background: Our VA research team has played a prominent role in documenting the significant skeletal muscle atrophy that accompanies chronic hemiparesis after disabling stroke. Muscle volume is reduced by 24% in paretic vs. non-paretic legs, having significant implications for strength, function, fitness, metabolism and general health. Our previous work establishes progressive, high-intensity resistive training (RT) as an effective rehabilitation strategy for oldr stroke survivors, producing thigh muscle hypertrophy on both the paretic and non-paretic sides. Protein supplementation can significantly augment gains in muscle mass after RT in healthy populations, but no experiments have yet been conducted in stroke. New preliminary data from our group indicates that stroke participants consume 20% less protein than the recommended daily amount for older individuals (0.80 vs. 1.0 g/kg/day) suggesting that relative gains in skeletal muscle could be significantly better in the presence of adequate protein intake. New data also indicates that leg muscle mass predicts resting metabolic rate (RMR) in stroke, implying that a combined nutrition and RT therapy aimed at maximizing muscle gains would translate into improved energy balance, a key factor in rehabilitation success. A better understanding of the true potential for aggressive RT interventions to address stroke-related atrophy and related problems for maximum benefit awaits clinical trials directly comparing RT with and without nutritional therapy. Objectives: We propose to be the first to conduct a 12-week randomized placebo controlled clinical trial comparing the effects of RT+ protein supplementation at 1.2 g/kg/day (RT+PRO) vs. RT+isocaloric placebo (RT+PLA) on body composition, hypertrophy regulation, strength, muscle quality, functional mobility and energy expenditure in chronic stroke. Aim 1: Compare effects of 12 weeks RT+PRO and RT+PLA on whole body lean tissue mass by DXA and thigh region muscle volume by CT. Aim 2: Assess changes to key regulators of skeletal muscle mass (myostatin, mTOR and their downstream signaling network) in RT+PRO vs. RT+PLA in stroke survivors. Aim 3: Determine the effects of RT+PRO and RT+PLA on leg strength, strength per unit muscle volume (muscle quality, MQ), functional mobility (6-minute walk distance, 10-meter walk time), RMR and free-living physical activity by 5-day accelerometry. Methods: To accomplish aims, 88 hemiparetic ischemic stroke subjects aged 40-85 years, BMI 20-40 kg/m2 will be randomized to either 3x/week RT+PRO or RT +PLA (equal calories for supplements) with nutritional counseling in both groups. Subjects will undergo strength and fitness tests, body composition scans, bilateral skeletal muscle biopsies, functional outcomes tests and energy expenditure assessments before and after 3 months of RT+PRO or RT+PLA. Impact: The proposed Merit study has clinical and practical implications for Veterans su...