{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T17:33:24Z","timestamp":1793122404754,"version":"4.5.0"},"reference-count":38,"publisher":"SAGE Publications","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JND"],"published-print":{"date-parts":[[2020,9,18]]},"abstract":"<jats:p>Background: Individuals with spinal muscular atrophy (SMA) III walk independently, but experience muscle weakness, gait impairments, and fatigue. Although SMA affects proximal more than distal muscles, the characteristic pattern of selective muscle weakness has not been explained. Two theories have been proposed: 1) location of spinal motor neurons; and 2) differences in segmental innervation. Objective: To identify neuroanatomical models that explain the selective muscle weakness in individuals with SMA and assess the relationship of these models to ambulatory function. Methods: Data from 23 ambulatory SMA participants (78.2% male), ages 10\u201356 years, enrolled in two clinical studies (NCT01166022, NCT02895789) were included. Strength was assessed using the Medical Research Council (MRC) score; ambulatory function was measured by distance walked on the 6-minute walk test (6\u200aMWT). Three models were identified, and relationships assessed using Pearson correlation coefficients and linear regression. Results: All models demonstrated a positive association between strength and function, (p\u200a&lt;\u200a0.02). Linear regression revealed that Model 3B, consisting of muscles innervated by lower lumbar and sacral segments, explained 67% of the variability observed in 6\u200aMWT performance (\u03b2=\u200a0.670, p\u200a=\u200a0.003). Conclusions: Muscles innervated by lower lumbar and sacral segments, i.e. hip extensors, hip abductors, knee flexors and ankle dorsiflexors, correlated with and predicted greater ambulatory function. The neuroanatomical patterns of muscle weakness may contribute to a better understanding of disease mechanisms and enable delivery of targeted therapies.<\/jats:p>","DOI":"10.3233\/jnd-200550","type":"journal-article","created":{"date-parts":[[2020,9,8]],"date-time":"2020-09-08T10:45:03Z","timestamp":1599561903000},"page":"459-466","source":"Crossref","is-referenced-by-count":4,"title":["Neuroanatomical Models of Muscle Strength and Relationship to Ambulatory Function in Spinal Muscular Atrophy"],"prefix":"10.1177","volume":"7","author":[{"given":"Rafael","family":"Rodriguez-Torres","sequence":"first","affiliation":[{"name":"Department of Rehabilitation and Regenerative Medicine, Columbia University Irving Medical Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Fabiano","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation and Regenerative Medicine, Columbia University Irving Medical Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Goodwin","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation and Regenerative Medicine, Columbia University Irving Medical Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashwini K.","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation and Regenerative Medicine, Columbia University Irving Medical Center, New York, NY, USA"},{"name":"G.H. 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Disorders. In: Darras B, H. Royden Jones J, Ryan MM, De Vivo D, editors. Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician\u2019s Approach. 2 ed. San Diego, CA: Academic Press; 2015. p. 117-20."},{"key":"10.3233\/JND-200550_ref25","doi-asserted-by":"crossref","first-page":"102002","DOI":"10.1016\/j.nicl.2019.102002","article-title":"Magnetic resonance imaging of the cervical spinal cord in spinal muscular atrophy","volume":"24","author":"Stam","year":"2019","journal-title":"Neuroimage Clin"},{"key":"10.3233\/JND-200550_ref26","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.nbd.2017.09.005","article-title":"ERK and ROCK functionally interact in a signaling network that is compensationally upregulated in Spinal Muscular Atrophy","volume":"108","author":"Hensel","year":"2017","journal-title":"Neurobiol Dis"},{"issue":"4","key":"10.3233\/JND-200550_ref27","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1007\/s00415-019-09646-w","article-title":"MRI patterns of muscle involvement in type 2 and 3 spinal muscular atrophy patients","volume":"267","author":"Brogna","year":"2020","journal-title":"J Neurol"},{"issue":"13","key":"10.3233\/JND-200550_ref28","doi-asserted-by":"crossref","first-page":"3767","DOI":"10.1016\/j.celrep.2017.12.003","article-title":"Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy","volume":"21","author":"Simon","year":"2017","journal-title":"Cell Rep"},{"issue":"16","key":"10.3233\/JND-200550_ref29","doi-asserted-by":"crossref","first-page":"2552","DOI":"10.1093\/hmg\/ddn156","article-title":"Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy","volume":"17","author":"Kariya","year":"2008","journal-title":"Hum Mol Genet"},{"issue":"4","key":"10.3233\/JND-200550_ref30","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/0022-510X(73)90169-X","article-title":"A comparison of fibre size, fibre type constitution and spatial fibre type distribution in normal human muscle and in muscle from cases of spinal muscular atrophy and from other neuromuscular disorders","volume":"20","author":"Johnson","year":"1973","journal-title":"J Neurol Sci"},{"issue":"3","key":"10.3233\/JND-200550_ref31","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/0887-8994(93)90082-N","article-title":"Prospective study of spinal muscular atrophy before age 6 years","volume":"9","author":"Iannaccone","year":"1993","journal-title":"DCN\/SMA Group. Pediatr Neurol"},{"issue":"3","key":"10.3233\/JND-200550_ref32","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/S0370-4475(83)80042-2","article-title":"[Electromyographic study of 50 cases of Werdnig-Hoffmann disease]","volume":"13","author":"Renault","year":"1983","journal-title":"Rev Electroencephalogr Neurophysiol Clin"},{"issue":"3","key":"10.3233\/JND-200550_ref33","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1172\/JCI131989","article-title":"Muscle-specific SMN reduction reveals motor neuron-independent disease in spinal muscular atrophy models","volume":"130","author":"Kim","year":"2020","journal-title":"J Clin Invest"},{"issue":"10213","key":"10.3233\/JND-200550_ref34","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.1016\/S0140-6736(19)32910-1","article-title":"Muscular dystrophies","volume":"394","author":"Mercuri","year":"2019","journal-title":"Lancet"},{"issue":"7","key":"10.3233\/JND-200550_ref35","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/S0003-9993(95)80629-6","article-title":"Strength training in patients with myotonic dystrophy and hereditary motor and sensory neuropathy: A randomized clinical trial","volume":"76","author":"Lindeman","year":"1995","journal-title":"Arch Phys Med Rehabil"},{"issue":"8","key":"10.3233\/JND-200550_ref36","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1016\/j.apmr.2003.12.025","article-title":"Resistance training effectiveness in patients with Charcot-Marie-Tooth disease: Recommendations for exercise prescription","volume":"85","author":"Chetlin","year":"2004","journal-title":"Arch Phys Med Rehabil"},{"issue":"8","key":"10.3233\/JND-200550_ref37","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1177\/0883073807305788","article-title":"Consensus statement for standard of care in spinal muscular atrophy","volume":"22","author":"Wang","year":"2007","journal-title":"J Child Neurol"},{"issue":"4","key":"10.3233\/JND-200550_ref39","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1002\/mus.24568","article-title":"Resistance strength training exercise in children with spinal muscular atrophy","volume":"52","author":"Lewelt","year":"2015","journal-title":"Muscle Nerve"},{"issue":"4","key":"10.3233\/JND-200550_ref40","doi-asserted-by":"crossref","first-page":"463","DOI":"10.3233\/JND-150101","article-title":"Single-Blind, Randomized, Controlled Clinical Trial of Exercise in Ambulatory Spinal Muscular Atrophy: Why are the Results Negative?","volume":"2","author":"Montes","year":"2015","journal-title":"J Neuromuscul Dis"}],"container-title":["Journal of Neuromuscular Diseases"],"original-title":[],"link":[{"URL":"https:\/\/content.iospress.com\/download?id=10.3233\/JND-200550","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T23:49:32Z","timestamp":1777506572000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/full\/10.3233\/JND-200550"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,18]]},"references-count":38,"journal-issue":{"issue":"4"},"URL":"https:\/\/doi.org\/10.3233\/jnd-200550","relation":{},"ISSN":["2214-3599","2214-3602"],"issn-type":[{"value":"2214-3599","type":"print"},{"value":"2214-3602","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,18]]}}}