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Submaximal exercise (SME) at 40% W<jats:sub>peak<\/jats:sub> was performed for 10\u00a0minutes. Change in vastus lateralis deoxygenated hemoglobin, measured by near\u2010infrared spectroscopy, determined muscle oxygen uptake (\u0394HHb) at rest and during CPET and SME. Dual energy X\u2010ray absorptiometry assessed fat\u2010free mass (FFM%). Fatigue was determined by percent change in workload or distance in the first compared to the last minute of SME (Fatigue<jats:sub>SME<\/jats:sub>) and six\u2010minute walk test (Fatigue<jats:sub>6MWT<\/jats:sub>), respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>\u0394HHb\u2010PEAK, \u0394HHb\u2010SME, VO<jats:sub>2peak<\/jats:sub>, W<jats:sub>peak<\/jats:sub>, FFM%, and 6MWT distance were lower (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), and Fatigue<jats:sub>6MWT<\/jats:sub> and Fatigue<jats:sub>SME<\/jats:sub> were higher (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) in SMA compared to controls. \u0394HHb\u2010PEAK correlated with FFM% (<jats:italic>r<\/jats:italic>\u00a0=\u00a00.50) and VO<jats:sub>2peak<\/jats:sub> (<jats:italic>r<\/jats:italic>\u00a0=\u00a00.41) only in controls. Only in SMA, Fatigue<jats:sub>6MWT<\/jats:sub> was inversely correlated with W<jats:sub>peak<\/jats:sub> (<jats:italic>r<\/jats:italic>\u00a0=\u00a0\u22120.69), and Fatigue<jats:sub>SME<\/jats:sub> was inversely correlated with FFM% (<jats:italic>r<\/jats:italic>\u00a0=\u00a0\u22120.55) and VO<jats:sub>2peak<\/jats:sub> (<jats:italic>r<\/jats:italic>\u00a0=\u00a0\u22120.69).<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>This study provides further support for muscle mitochondrial dysfunction in SMA patients. During exercise, we observed diminished muscle oxygen uptake but no correlation with aerobic capacity or body composition. We also observed increased fatigue which correlated with decreased aerobic capacity, workload, and body composition. Understanding the mechanisms underlying diminished muscle oxygen uptake and increased fatigue during exercise in SMA may identify additional therapeutic targets that rescue symptomatic patients and mitigate their residual disease burden.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51353","type":"journal-article","created":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T11:45:17Z","timestamp":1617191117000},"page":"1086-1095","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Diminished muscle oxygen uptake and fatigue in spinal muscular atrophy"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7357-0819","authenticated-orcid":false,"given":"Jacqueline","family":"Montes","sequence":"first","affiliation":[{"name":"Department of Rehabilitation and Regenerative Medicine Columbia University Irving Medical Center  New York New York USA"},{"name":"Department of Neurology Columbia 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