Activation of the Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase (SERCA) as a Therapeutic Intervention for Sarcopenia

激活肌浆/内质网钙 ATP 酶 (SERCA) 作为肌肉减少症的治疗干预措施

基本信息

批准号：
10454863
负责人：
HOLLY VAN REMMEN
金额：
--
依托单位：
OKLAHOMA CITY VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454863
关键词：
ATP phosphohydrolase Affect Age-Months Aging Atrophic Back Biological Biological Assay Ca(2+)-Transporting ATPase Calcium Calcium Signaling Cell physiology Data Denervation Diet Dose Drug Kinetics Effectiveness of Interventions Elderly Endoplasmic Reticulum Ensure Enzymes Female Gene Expression Generations Goals Health Care Costs Homeostasis Hour Human Impairment Independent Living Intake Intervention Laboratories Lead Living Costs Maintenance Measures Membrane Metabolic Metabolism Mitochondria Modeling Mus Muscle Muscle Contraction Muscle Mitochondria Muscle Weakness Muscle function Muscular Atrophy Mutant Strains Mice Oral Administration Oxidative Stress Peptide Hydrolases Pharmaceutical Preparations Pharmacological Treatment Pharmacology Phenotype Plasma Pre-Clinical Model Production Proteolysis Pump Quality of life Regulation Reporting Reticulum Sarcoplasmic Reticulum Skeletal Muscle Testing Therapeutic Intervention Tissues Veterans Wild Type Mouse Work age related age-related muscle loss antioxidant enzyme cognitive function copper zinc superoxide dismutase disability enzyme activity follow-up frailty healthspan improved in vivo inhibitor male mouse model muscle form muscle strength novel therapeutic intervention prevent response restoration sarcolipin sarcopenia skeletal muscle wasting successful intervention superoxide dismutase 1 transcriptome sequencing young adult

项目摘要

Sarcopenia (loss of muscle mass and function) universally affects the elderly and has a tremendous impact on quality of life, independent living, and healthcare costs in aging veterans. The goal of this study is to test a potential new pharmacological approach, activation of the sarcoendoplasmic reticulum (SR) calcium ATPase (SERCA) that pumps Ca2+ back into the SR following muscle contraction, to modulate sarcopenia. This work is critically important as no effective pharmacologic interventions currently exist. Here we have employed a mouse model of sarcopenia developed by my laboratory (the Sod1-/- mouse lacking the antioxidant enzyme CuZnSOD) that recapitulates many features of sarcopenia in aging mice and in humans as a pre-clinical model to test and characterize potential interventions. Successful interventions can then be tested further in aging wild type mice. Disrupted intracellular calcium homeostasis is a potential contributor to loss of skeletal muscle mass and force-generating capacity during aging and impaired SERCA function can lead to elevated cytosolic calcium and deleterious effects on cellular processes. We hypothesized that increasing SERCA activity to maintain calcium homeostasis may be an effective mechanism to treat sarcopenia. In support of this, our preliminary data clearly show that treatment of 2 month old Sod1-/- mice with CDN1163, an allosteric SERCA activator, increases SERCA activity, blunts muscle atrophy, improves force generation and reduces muscle mitochondrial ROS production that occurs in the untreated Sod1-/- mice. CDN1163 has reported beneficial effects on metabolism and cognitive function, but our study is the first to test its application as a therapeutic intervention for treating sarcopenia. In this proposal, we will test the hypothesis that SERCA activation can prevent/reduce muscle atrophy and weakness through regulation of cytosolic calcium signaling, mitochondrial function and reduced proteolytic activity. First, we will define dose response and biologic effects of oral administration of CDN1163 in mice through the diet. Once we have determined an optimal effective dose, we will follow up on our exciting data and test whether CDN1163 treatment can prevent/reduce age-related loss of muscle mass and weakness in aging wild type mice in Aim 2. Male and female wildtype C57Bl6 mice will be administered CDN1163 starting at 15 months of age. We will measure the effect of CDN1163 treatment on the regulation of cytosolic calcium signaling, mitochondrial function, contractile function, reduced proteolytic activity and other essential markers of the sarcopenia phenotype at 15, 20, and 28 months of age. SERCA activity is also regulated by an endogenous inhibitor, sarcolipin (Sln). Our studies have shown that sarcolipin is elevated in muscle during aging and in Sod1-/- mice, consistent with reduced SERCA activity. In Aim 3, we will test whether activation of SERCA through depletion of the SERCA inhibitor sarcolipin modulates sarcopenia in aging Sln-/- mutant mice. We will measure markers of muscle mass, muscle quality, contractile function and metabolic function in response to sarcolipin depletion in 6, 18 and 28 month old male and female wild type and Sln-/- mice. If sarcolipin depletion activates SERCA and modulates muscle atrophy/weakness, this will further support the use of SERCA activators as a therapeutic intervention. Together, these studies have significant potential to reveal a new therapeutic intervention to modulate sarcopenia.

肌肉减少症（肌肉质量和功能丧失）普遍影响老年人，并且具有对老年退伍军人的生活质量、独立生活和医疗费用产生巨大影响。这项研究的目的是测试一种潜在的新药理学方法，即激活肌内质网 (SR) 钙 ATP 酶 (SERCA) 将 Ca2+ 泵回 SR 肌肉收缩后，调节肌肉减少症。这项工作至关重要，因为没有目前存在有效的药物干预措施。这里我们使用了一个小鼠模型我的实验室开发的肌肉减少症（缺乏抗氧化酶的 Sod1-/- 小鼠） CuZnSOD）概括了衰老小鼠和人类肌肉减少症的许多特征用于测试和表征潜在干预措施的临床前模型。成功的干预可以然后在衰老的野生型小鼠中进行进一步测试。细胞内钙稳态被破坏是衰老过程中骨骼肌质量和产生力的能力丧失的潜在因素 SERCA 功能受损会导致胞浆钙升高并对身体产生有害影响细胞过程。我们假设增加 SERCA 活性以维持钙体内平衡可能是治疗肌肉减少症的有效机制。为了支持这一点，我们的初步数据清楚地表明，用 CDN1163（一种变构 SERCA 激活剂，增加 SERCA 活性，减缓肌肉萎缩，提高力量生成并减少未经处理的肌肉线粒体 ROS 的产生 Sod1-/- 小鼠。 CDN1163 已报告对新陈代谢和认知功能有有益影响，但我们的研究是第一个测试其作为治疗干预的应用肌肉减少症。在这个提案中，我们将测试 SERCA 激活可以通过调节胞质钙信号传导来预防/减少肌肉萎缩和无力，线粒体功能和蛋白水解活性降低。首先，我们将定义剂量反应和通过饮食口服 CDN1163 对小鼠的生物学影响。一旦我们有确定最佳有效剂量后，我们将跟进我们令人兴奋的数据并测试是否 CDN1163 治疗可以预防/减少与年龄相关的肌肉质量损失和肌无力目标 2 中衰老的野生型小鼠。将给予雄性和雌性野生型 C57Bl6 小鼠 CDN1163 从 15 个月大时开始。我们将测量 CDN1163 治疗的效果细胞质钙信号传导、线粒体功能、收缩功能的调节，减少 15、20 和 28 时肌少症表型的蛋白水解活性和其他重要标志物月龄。 SERCA 活性还受到内源性抑制剂肌磷脂 (Sln) 的调节。我们的研究表明，衰老过程中以及 Sod1-/- 小鼠的肌肉中肌磷脂升高，与 SERCA 活性降低一致。在目标3中，我们将测试SERCA是否激活通过耗尽 SERCA 抑制剂肌磷脂调节衰老 Sln-/- 突变体中的肌肉减少症老鼠。我们将测量肌肉质量、肌肉质量、收缩功能和 6、18 和 28 个月大的男性和女性对肌磷脂消耗的代谢功能雌性野生型和 Sln-/- 小鼠。如果肌磷脂耗尽会激活 SERCA 并调节肌肉萎缩/虚弱，这将进一步支持 SERCA 激活剂作为治疗方法的使用干涉。总之，这些研究具有揭示新治疗方法的巨大潜力干预来调节肌肉减少症。