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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：
10166596
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/10166596
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/antagonist 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.

骨骼肌减少症（肌肉质量和功能的丧失）普遍影响老年人，并有一个严重的疾病