Skeletal Muscle Mitochondrial Dysfunction and Motor Unit Number in Sporadic ALS

描述(申请人提供)：散发性肌萎缩性侧索硬化症(SALS)是一种神经退行性疾病，以上下运动神经元为目标，导致运动单位丧失；严重的进行性肌肉萎缩；以及几乎不可避免的死亡。主要来自ALS动物模型的多条证据表明，骨骼肌氧化性ATP合成减少(线粒体功能障碍)在疾病过程的早期表现出来，可能有助于这些神经退化过程。然而，人类肌萎缩侧索硬化症患者是否存在骨骼肌线粒体功能障碍，以及它在神经退行性变中可能发挥的作用仍不明确。在人类SALS患者中检验骨骼肌线粒体功能障碍假说的局限性是迄今为止使用的主要技术是肌肉活组织检查和组织化学分析。由于取样量小，活组织检查技术容易出现假阴性，而且该技术的侵入性使其不适合用于以肌肉萎缩为特征的疾病。然而，磷磁共振波谱(31P-MRS)为评估体内线粒体功能提供了一种强有力的替代方法，已被成功地用于研究肌肉等其他病理条件下的线粒体功能，可以从局部解剖区域获得数据，并且是非侵入性和非破坏性的。因此，本项目的总体目标是使用31P-MRS来探索SALS患者骨骼肌线粒体功能障碍的存在和全身能量后果，并将这些线粒体功能指标与疾病状态的临床指标联系起来。为了实现这一目标，我们设定了以下具体目标：具体目标1：检验尽管SALS患者的静息能量消耗(REE)较高，但SALS患者和对照组的静息骨骼肌ATP合成率将相似的假设。为此，我们将在SALS患者和年龄、性别、体重指数(BMI)和体力活动匹配的对照组中，使用饱和转移31P-MRS和REE测量静息骨骼肌ATP合成率。具体目的2a：验证SALS患者骨骼肌最大有氧ATP合成率低于匹配对照组的假设。为此，我们将使用31P-MRS来测量SALS患者和匹配对照组在一系列最大等长收缩后的最大骨骼肌有氧ATP合成率。特定目标2b：验证SALS患者与健康对照组相比收缩的ATP成本较低的假设。为此，我们将使用31P-MRS测量SALS患者和匹配对照组的骨骼肌收缩的ATP成本。通过测试有关骨骼肌ATP合成与总能量消耗的解偶联(目标1)、ATP合成最大速率受损(目标2a)和收缩的能量成本(目标2b)的假设，拟议的研究将提供第一个已知的对人类SALS患者骨骼肌线粒体功能障碍的存在和性质的系统研究。 公共卫生相关性：散发性肌萎缩侧索硬化症(SALS)导致控制骨骼肌的神经崩溃，导致严重的肌肉萎缩。这些神经的死亡方式和原因尚不清楚；然而，这可能与骨骼肌利用氧气的能力缺陷有关。这项研究的目的是确定SALS患者的肌肉利用氧气的能力是否减弱，以及这是否与神经丢失有关。

DESCRIPTION (provided by applicant): Sporadic Amyotrophic lateral sclerosis (SALS) is a neurodegenerative disease that targets upper and lower motor neurons and causes motor unit loss; severe, progressive muscle atrophy; and almost inevitably, death. Multiple lines of evidence, derived primarily from animal models of ALS, suggest that reduced skeletal muscle oxidative ATP-synthesis ("mitochondrial dysfunction") manifests itself early in the disease process and may contribute to these neurodegenerative processes. However, whether or not skeletal muscle mitochondrial dysfunction is present in human ALS patients and what role it may play in neurodegeneration remains equivocal. A limitation to testing the hypothesis of skeletal muscle mitochondrial dysfunction in human SALS patients is the primary technique used to date is muscle biopsy followed by histochemical analysis. The biopsy technique is prone to false negatives, due to the small sampling volume, and the invasive nature of the technique makes it inappropriate for use in a disease marked by muscle wasting. However, phosphorus magnetic resonance spectroscopy (31P-MRS) provides a powerful alternative for assessing mitochondrial function in vivo, has been used successfully to study mitochondrial function in other pathological conditions involving muscle, can acquire data from localized anatomical regions, and is non- invasive and non-destructive. Therefore, the overall goal of this project is to use 31P-MRS to explore the presence and whole-body energetic consequences of skeletal muscle mitochondrial dysfunction in SALS patients and to relate these measures of mitochondrial function to clinical measures of disease state. In order to accomplish this objective, we have set the following specific aims: Specific Aim 1: To test the hypothesis that resting skeletal muscle ATP-synthesis rate will be similar in SALS patients and controls in spite of higher resting energy expenditure (REE) in SALS patients. To do so, we will measure resting skeletal muscle ATP- synthesis rate using saturation transfer 31P-MRS and REE using indirect calorimetry in SALS patients and age-, gender-, body mass index (BMI)-, and physical activity- matched controls. Specific Aim 2a: To test the hypothesis that maximum skeletal muscle aerobic ATP-synthesis rate will be lower in SALS patients than in matched controls. To do so, we will use 31P-MRS to measure maximum skeletal muscle aerobic ATP-synthesis rate following a series of maximal isometric contractions in SALS patients and matched controls. Specific Aim 2b: To test the hypothesis that the ATP cost of contraction is lower in SALS patients versus healthy controls. To do so, we will measure the ATP cost of skeletal muscle contractions in SALS patients and matched controls using 31P-MRS. By testing hypotheses concerning the uncoupling of skeletal muscle ATP-synthesis to total energy expenditure (Aim 1), impairments to the maximum rate of ATP-synthesis (Aim 2a), and the energetic cost of contraction (Aim 2b), the proposed studies will provide the first known systematic investigation of the presence and nature of skeletal muscle mitochondrial dysfunction in human SALS patients. PUBLIC HEALTH RELEVANCE: Sporadic Amyotrophic lateral sclerosis (SALS) results in break down of the nerves that control skeletal muscle, resulting in severe muscle wasting. How and why these nerves die remains unclear; however, it may be related to a defect in the skeletal muscles' ability to use oxygen. The aim of this study is to determine if the muscles of SALS patients have a diminished capacity to use oxygen and if this is related to nerve loss.