Noninvasive assessment of skeletal muscle integrity and function with statin use

使用他汀类药物对骨骼肌完整性和功能进行无创评估

• 批准号: 7467848
• 负责人: Jill M Slade
• 金额: $ 20.03万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-26 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7467848
• 关键词: Adverse effects; Aerobic; Age; Anterior; Apoptosis; Atorvastatin calcium; Attenuated; Biopsy; Blood; Blood Vessels; Calcium; Cell Respiration; Cell membrane; Cells; Cholesterol; Class; Complex; Condition; Creatine Kinase; Data; Disease; Disruption; Distal; Enzymes; Exercise; Exercise Physiology; Fibromyalgia; Flexor; Health; Hip region structure; Image; Individual; Invasive; Knee; Laboratories; Leg; Lipids; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mediating; Metabolism; Mitochondria; Mitochondrial Myopathies; Monitor; Muscle; Muscle Cells; Muscle Fatigue; Muscle Fibers; Muscle Weakness; Muscle function; Muscular Dystrophies; Myalgia; Myopathy; Nuclear Magnetic Resonance; Numbers; Pain; Patients; Personal Satisfaction; Pharmaceutical Preparations; Phosphocreatine; Phosphorus; Physicians; Pilot Projects; Population; Post-Translational Protein Processing; Predisposition; Prevalence; Procedures; Protons; Public Health; Rate; Recovery; Red Fiber; Reporting; Research Design; Respiratory Chain; Rest; Rhabdomyolysis; Serum; Skeletal Muscle; Skeletal system; Spectrum Analysis; Testing; Time; Upper arm; Week; Whole Blood; ankle joint dorsiflexor; biceps brachii muscle; cholesterol biosynthesis; dosage; functional decline; functional disability; heart disease risk; indexing; lipoprotein cholesterol; molecular imaging; muscle strength; novel; nutrition; phosphodiester; phosphoric diester hydrolase; repaired; satellite cell; tumor

DESCRIPTION (provided by applicant): Statins are a class of cholesterol lowering medications proven effective for attaining healthy cholesterol and lipoprotein levels, while also indicated for a number of other health conditions, e.g. lowering heart disease risk, vascular protection. As a result, statin use has increased in recent years. Skeletal muscle weakness and pain are occasional side effects of statin use (1-7%) and in rare cases severe muscle destruction (rhabdomyolysis) may result. Accumulating evidence suggests that the prevalence of statin effects on skeletal muscle may very well be underestimated. Statins can cause structural and functional impairments in skeletal muscle by inhibiting cholesterol synthesis and the intermediate products. Statin effects include myocyte apoptosis, decreased cell membrane integrity, mitochondrial myopathy, diminished cytoskeletal integrity and diminished muscle repair. These may consequently result in reduced muscle function including strength loss, increased susceptibility to damage, and diminished muscle aerobic metabolism. Currently serum creatine kinase (CK) or muscle biopsies are used to verify statin induced myopathy. While CK can be easily assessed, it is not necessarily elevated in statin users with myalgia or myopathy. In this pilot project, molecular imaging with NMR (nuclear magnetic resonance) will be used to measure skeletal muscle integrity and function before and during statin treatment. Aim 1 will examine the effect of statins on skeletal muscle cell membrane turnover by non-invasively measuring phosphorus metabolites with NMR, in particular muscle and blood phosphodiesterase (PDE). Elevated PDE appears in tumors as well as skeletal muscle of individuals with muscle related disorders presumably from increased cell turnover. Muscle PDE is also elevated in statin users. Aim 2 will examine the effects of statins on mitochondrial function by measuring the change in muscle aerobic capacity primarily with phosphorus NMR and muscle fatigue. Aim 3 will examine the effect of statins on skeletal muscle function including changes in maximal strength and muscle damage (with NMR). Twenty-five healthy individuals will be tested before and during 4 weeks of statin use (80-mg atorvastatin calcium). Aims 1 and 3 will also be evaluated in a patient population. Through this pilot study we will determine the utility of using NMR to non-invasively assess statin- induced myopathy and to quantify muscle functional declines with statin use. NMR may be particularly relevant for identifying individuals for whom the benefits of statins might otherwise be blunted by muscle effects. PUBLIC HEALTH RELEVANCE. With the widespread and ever increasing use of statins (cholesterol lowering medications), there is a true need to understand the side effects of statin use including the true functional consequences to skeletal muscle. These studies are designed to measure changes in muscle health and function without using invasive procedures. In addition, these studies are designed to evaluate a novel measure of statin induced muscle problems.

描述（由申请人提供）：他汀类药物是一类降低胆固醇的药物，已被证明可有效达到健康的胆固醇和脂蛋白水平，同时也适用于许多其他健康状况，例如高血压。降低心脏病风险，保护血管。因此，近年来他汀类药物的使用有所增加。骨骼肌无力和疼痛是他汀类药物使用的偶尔副作用（1-7%），在极少数情况下可能会导致严重的肌肉破坏（横纹肌溶解症）。越来越多的证据表明，他汀类药物对骨骼肌的影响很可能被低估了。他汀类药物可以通过抑制胆固醇合成和中间产物来引起骨骼肌的结构和功能损伤。他汀类药物的作用包括心肌细胞凋亡、细胞膜完整性降低、线粒体肌病、细胞骨架完整性降低和肌肉修复减弱。这些可能会导致肌肉功能下降，包括力量损失、损伤敏感性增加以及肌肉有氧代谢减弱。目前，血清肌酸激酶（CK）或肌肉活检用于验证他汀类药物引起的肌病。虽然 CK 很容易评估，但在患有肌痛或肌病的他汀类药物使用者中，CK 不一定会升高。在这个试点项目中，核磁共振（NMR）分子成像将用于测量他汀类药物治疗之前和期间的骨骼肌完整性和功能。目标 1 将通过 NMR 无创测量磷代谢物，特别是肌肉和血液磷酸二酯酶 (PDE)，来检查他汀类药物对骨骼肌细胞膜更新的影响。 PDE 升高出现在肿瘤以及患有肌肉相关疾病的个体的骨骼肌中，可能是由于细胞更新增加所致。他汀类药物使用者的肌肉 PDE 也会升高。目标 2 将通过主要通过磷 NMR 和肌肉疲劳测量肌肉有氧能力的变化来检查他汀类药物对线粒体功能的影响。目标 3 将检查他汀类药物对骨骼肌功能的影响，包括最大力量和肌肉损伤的变化（使用 NMR）。将在使用他汀类药物（80 毫克阿托伐他汀钙）之前和使用他汀类药物 4 周期间对 25 名健康个体进行测试。目标 1 和 3 还将在患者群体中进行评估。通过这项试点研究，我们将确定使用 NMR 来非侵入性评估他汀类药物引起的肌病并量化他汀类药物使用引起的肌肉功能下降的效用。核磁共振对于识别他汀类药物的益处可能会因肌肉效应而减弱的个体尤其重要。 公共卫生相关性。随着他汀类药物（降胆固醇药物）的广泛使用和不断增加，确实需要了解他汀类药物使用的副作用，包括对骨骼肌的真正功能影响。这些研究旨在在不使用侵入性手术的情况下测量肌肉健康和功能的变化。此外，这些研究旨在评估他汀类药物引起的肌肉问题的新方法。