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 resulting in developmental disability. Consistent with the mission of the Eunice Kennedy Schriever National Institute of Child Health and Development, this project addresses important disease related disabilities and will help direct future medical rehabilitation programs.

Public Health Relevance

SMA is the second most common genetically determined disease of childhood resulting in significant disability with no known effective drug treatment. With improved medical care, life expectancy for SMA type 3 is thought to no longer differ from that of the general population. As a result, maximizing fitness, endurance, general health and well-being, in an effort to modulate the disease and potential comorbidity, are important goals in this population.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01HD084690-02
Application #
9323491
Study Section
National Institute of Child Health and Human Development Initial Review Group (CHHD)
Program Officer
Nitkin, Ralph M
Project Start
2016-08-01
Project End
2021-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Physical Medicine & Rehab
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Montes, Jacqueline; McDermott, Michael P; Mirek, Elizabeth et al. (2018) Ambulatory function in spinal muscular atrophy: Age-related patterns of progression. PLoS One 13:e0199657
Montes, Jacqueline; Zanotto, Damiano; Dunaway Young, Sally et al. (2017) Gait assessment with solesound instrumented footwear in spinal muscular atrophy. Muscle Nerve 56:230-236