Evaluation of Oxidative Capacity and Exercise Tolerance in Ambulatory Patients with Spinal Muscular Atrophy

脊髓性肌萎缩症门诊患者氧化能力和运动耐量的评估

• 批准号: 9906070
• 负责人: Jacqueline Montes
• 金额: $ 12.96万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906070
• 关键词: Acute; Address; Adult; Aerobic; Affect; Ankle; Biogenesis; Biolectric Impedance; Body Composition; Caring; Child; Child Development; Child Health; Childhood; Chromosomes; Clinical; Clinical assessments; Control Groups; Data; Data Collection; Developmental Disabilities; Disease; Dual-Energy X-Ray Absorptiometry; Ergometry; Evaluation; Exercise; Exercise Therapy; Exercise Tolerance; Extensor; Flexor; Future; General Population; Goals; Health; Individual; Institutes; Intervention; Intervention Studies; Knee; Laboratories; Leg; Life Expectancy; Manuals; Medical; Mission; Mitochondria; Mitochondrial DNA; Mitochondrial Myopathies; Molecular; Motor Neuron Disease; Muscle; Muscle function; Mutation; Near-Infrared Spectroscopy; Neuromuscular Diseases; Neuromuscular conditions; Observational Study; Participant; Patients; Personal Satisfaction; Pharmacotherapy; Phenotype; Physiological; Population; Population Control; Proteins; Rehabilitation therapy; Research Project Grants; Severity of illness; Spinal Muscular Atrophy; Testing; Therapeutic Intervention; Thinness; Time; Tissues; Training; Visit; Walking; burden of illness; clinical phenotype; comorbidity; comparison group; conditioning; deconditioning; design; disability; disorder control; exercise capacity; exercise intervention; exercise intolerance; exercise program; exercise training; fitness; gait examination; improved; in vivo; lean body mass; muscle strength; programs; public health relevance; reduced muscle mass; response; survival motor neuron gene; targeted treatment

 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 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.

 描述（由适用提供）：拟议的研究项目将集中于脊柱肌肉萎缩（SMA）患者运动能力降低的病理生理基础。 SMA的卧床患者的氧化能力显着降低，并且对运动的调节反应钝化。相反，其他神经肌肉疾病从具有相似的临床表现和功能限制的有氧调节目的地的运动计划中获得了重大益处。有实验室证据表明，线粒体生物发生的基础机制可能容易受到SMN缺乏症的影响。氧化能力的降低与瘦质量和疾病严重程度不成比例，将进一步支持SMA线粒体部署的证据。可能需要采取替代运动训练策略和/或伴随的有针对性的治疗干预措施才能达到有氧运动效果。了解腿部肌肉群体组成和氧化能力的潜在差异将允许开展运动训练范式利用最适合的肌肉群体，以引起训练效果。该提案将重点放在（1）使用近红外光谱法和（2）描述身体组成的情况下，在运动过程中估算特定肌肉群的氧化能力，以更好地了解ABSURATON SMA患者和疾病对照中的运动能力和线粒体功能。这是一项为期6个月的观察性研究，其中包括14名卧床性SMA患者，14例卧床性肌病患者和14个健康对照。线粒体肌病患者是理想的疾病控制人群，因为虽然线粒体在疾病和表型上都暗示，但它们可能同样地呈现，但导致运动摄入的机制却不同。在临床上，线粒体患者是理想的疾病比较，因为（1）它们代表广泛的表型谱，（2）包括儿童和成人，并且（3）在使用循环测量法的先前研究中表现出有氧调节的好处。所有参与者将进行两次访问，分别为6个月，以进行评估和数据收集。访问评估将包括在次最大运动过程中近乎腿部肌肉群的近红外光谱，以确定氧化物能力。同一肌肉群的双能X射线绝对心理学（DEXA）和节段生物电阻抗分析（BIA）将用于评估人体组成。其他临床评估将包括运动耐受性测试，六分钟步行测试（6MWT），包括收集分析，定时和进行进行测试，以及对腿部肌肉组的手动和定量强度评估。必须对强度和功能进行临床评估，以量化疾病严重程度和与疾病伯恩的物理评估进行比较。 SMA是影响儿童导致发育障碍的最常见遗传确定的神经肌肉疾病之一。与尤尼斯·肯尼迪·施里弗国家儿童发展与发展研究所的任务一致，该项目涉及与疾病有关的重要疾病，并将有助于指导未来的医疗康复计划。

项目成果

Neuroanatomical Models of Muscle Strength and Relationship to Ambulatory Function in Spinal Muscular Atrophy.

• DOI: 10.3233/jnd-200550
• 发表时间: 2020
• 期刊: JOURNAL OF NEUROMUSCULAR DISEASES
• 影响因子: 3.3
• 作者: Rodriguez-Torres, Rafael;Fabiano, Julia;Goodwin, Ashley;Rao, Ashwini K.;Kinirons, Stacy;De Vivo, Darryl;Montes, Jacqueline
• 通讯作者: Montes, Jacqueline

Ambulatory function in spinal muscular atrophy: Age-related patterns of progression.

• DOI: 10.1371/journal.pone.0199657
• 发表时间: 2018
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Montes J;McDermott MP;Mirek E;Mazzone ES;Main M;Glanzman AM;Duong T;Young SD;Salazar R;Pasternak A;Gee R;De Sanctis R;Coratti G;Forcina N;Fanelli L;Ramsey D;Milev E;Civitello M;Pane M;Pera MC;Scoto M;Day JW;Tennekoon G;Finkel RS;Darras BT;Muntoni F;De Vivo DC;Mercuri E
• 通讯作者: Mercuri E