Single-Blind, Randomized, Controlled Clinical Trial of Exercise in Ambulatory Spinal Muscular Atrophy: Why are the Results Negative?

Abstract

Background:The benefits of exercise on long-term health and well-being are well established. The possible benefits of exercise in Spinal Muscular Atrophy (SMA) have not been explored in a controlled clinical trial format.Objective:To assess the effects of exercise on measures of function, strength, and exercise capacity in ambulatory SMA patients.Methods:Fourteen participants, ages 10–48 years, were randomized to control and exercise cohorts after a 1 month lead-in period. The exercise group received 6 months of intervention. Thereafter, both groups received the intervention for the remaining 12 months. Participants were monitored for a total of 19 months. Exercise included individualized home-based cycling and strengthening. The primary outcome measure was distance walked during the six-minute walk test (6MWT). Secondary outcomes included strength, function, exercise capacity, quality of life and fatigue.Results:Twelve participants completed the first 7 months of the study, and 9 completed all 19 months. At baseline, the groups were similar on all clinical variables. There were no group changes at any time point in the 6MWT, fatigue, or function. Percent-predicted VO2 max improved 4.9% in all participants in 6 months (p = 0.036) (n = 10).Conclusion:Daily exercise is safe in ambulatory SMA and should be encouraged. We did not uncover any deleterious effects on strength, function, or fatigue. Our study documented a reduction in oxidative capacity and a blunted conditioning response to exercise possibly representing an important insight into underlying pathophysiological mechanisms. These findings also may be linked causally to mitochondrial depletion in SMA and warrant further study.

Six-minute walk test is reliable and valid in spinal muscular atrophy

“…A limitation in 1 or more body systems will result in reduced exercise tolerance, but this reflects physical capacity. Ambulant SMA patients have lower exercise capacity compared with age‐ and gender‐based norms, and this is believed to be secondary to reduced muscle power and cardiorespiratory fitness, consistent with severe deconditioning and possible impairments in muscle oxidative capacity . This was well represented in our sample.…”

“…Maximal effort for all participants was verified as volitional fatigue defined by at least 2 of the following criteria: (1) OMNI Ratings of Perceived Exertion Scale ≥8/10; (2) inability to maintain pedal cadence at 50 rpm for 10 or more seconds; or (3) respiratory exchange ratio (RER; carbon dioxide production/ oxygen uptake > 1.0) . Exercise tolerance testing provides an objective evaluation of overall fitness and is considered the best paradigm for assessing aerobic conditioning in diverse patient populations, including neuromuscular disease, and this procedure was previously described in SMA …”

Impaired Muscle Mitochondrial Biogenesis and Myogenesis in Spinal Muscular Atrophy

“…Recent clinical observations reporting an incomplete response to aerobic exercise in patients with SMA also sustain this scenario. 57 …”

Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care

“…In a recent study on sitters and walkers, functional changes over 12 months were minimal in the whole cohort and the few outliers showing a more substantial loss of functional activities were often those with increase in their joint contractures, sudden scoliosis deterioration or excessive weight gain [36]. Other papers have reported the benefits of braces, orthoses and exercise [38][39][40][41][42][43][44][45] (Supplementary Table S3).…”