DESCRIPTION (provided by applicant): The proposed research project will focus on the pathophysiological underpinnings of reduced exercise capacity in patients with Spinal Muscular Atrophy (SMA). Ambulatory patients with SMA have a marked reduction in oxidative capacity and a blunted conditioning response to exercise. In contrast, other neuromuscular conditions derive significant benefit from exercise programs of aerobic conditioning despite having similar clinical presentations and functional limitations. There has been laboratory evidence to suggest that the molecular mechanisms underlying mitochondrial biogenesis may be vulnerable to SMN deficiency. A reduction in oxidative capacity disproportionate to lean mass and disease severity would further support evidence of mitochondrial depletion in SMA. Alternative exercise training strategies and/ or concomitant targeted therapeutic intervention may be necessary to achieve an aerobic conditioning effect. Understanding potential differences in composition and oxidative capacity among leg muscle groups will permit directed exercise training paradigms exploiting muscle groups most amenable to elicit a training effect. This proposal will focus on (1) estimating oxidative capacity of specific muscle groups during exercise using near infrared spectroscopy and (2) describing body composition to better understand exercise capacity and mitochondrial function in ambulatory SMA patients and disease controls. It is a 6-month observational study including 14 ambulatory SMA patients, 14 ambulatory patients with mitochondrial myopathy, and 14 healthy controls. Mitochondrial myopathy patients serve as the ideal disease control population because while the mitochondria is implicated in both disorders and phenotypically they may present similarly, the mechanism causing exercise intolerance is different. Clinically, mitochondrial patients are the ideal disease comparison because (1) they represent a broad phenotypic spectrum, (2) include children and adults, and (3) have demonstrated benefit to aerobic conditioning in previous studies using cycle ergometry. All participants will undergo two visits, 6 months apart, for assessment and data collection. Visit assessments will include near infra-red spectroscopy of leg muscle groups during submaximal exercises to determine oxidative capacity. Dual energy x-ray absorptiometry (DEXA) and segmental bioelectrical impedance analysis (BIA) of the same muscle groups will be used to evaluate body composition. Additional clinical assessments will include exercise tolerance testing, the six minute walk test (6MWT) with gait analysis, timed up and go test, and manual and quantitative strength assessments of leg muscle groups. Clinical assessments of strength and function are necessary to quantify disease severity and for comparison to physiological assessments of disease burden. SMA is one of the most common genetically determined neuromuscular disorders affecting children res...