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Calcium Leak-Dependent Muscle Function Loss in Aged C elegans

老年秀丽隐杆线虫钙泄漏依赖性肌肉功能丧失

基本信息

批准号：
9051845
负责人：
Frances Margaret Forrester
金额：
$ 4.31万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9051845
关键词：
Actins Age Aging American Binding Caenorhabditis elegans Caffeine Calcium Cell physiology Censuses Coupled Coupling Custom Deterioration Dissection Dissociation Drug Targeting Dyes Elderly Electron Transport Endoplasmic Reticulum Free Radicals Functional disorder Future Genetic Models Goals Health Homologous Gene Human Image Immunoblotting Immunoprecipitation Ions Lead Learning Life Locomotion Longevity Measures Mediating Membrane Proteins Mitochondria Modeling Morbidity - disease rate Mus Muscle Muscle Contraction Muscle Proteins Muscle Weakness Muscle function Myosin ATPase Nematoda Physiology Play Population Post-Translational Protein Processing Prevalence Probability Production Protein Biochemistry Reactive Oxygen Species Research Research Personnel Role RyR1 Ryanodine Receptor Calcium Release Channel Ryanodine Receptors Sarcoplasmic Reticulum Source Swimming Techniques Testing Time Training Tropomyosin Troponin C age related aged bone career cell motility defined contribution fall risk genetic approach genetic regulatory protein improved mitochondrial membrane muscle aging muscle form mutant novel therapeutics oxidation public health relevance research study sarcopenia therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Sarcopenia, defined as an age-related loss of muscle mass and function, is a burgeoning health problem with a prevalence as high as 30% in the geriatric population. Current treatments have low long- term efficacy and do not target any underlying causes of muscle function loss. Recent research in aged mice in our lab has implicated the Ryanodine Receptor (RyR1), an intracellular calcium release channel important for excitation-contraction coupling, as a potential therapeutic target. Over time, RyR1 undergoes posttranslational modification ('remodeling') that causes calstabin1, an important RyR1 modulatory subunit, to dissociate from the channel; this results in increased RyR1 open probability and Ca2+ 'leak'. This Ca2+ 'leak' cause nearby mitochondria to overload with calcium and produce excess reactive oxygen species (ROS), which exacerbate the leak by further remodeling RyR1. Due to the relatively long lifespan of mice we were testing if C. elegans could serve as a better model of age- dependent muscle function loss. C. elegans contain UNC-68, the RyR1 homologue, and FKB-2, a calstabin homologue; therefore, we hypothesize that 1) FKB-2 dissociation destabilizes UNC-68 channels, resulting in pathogenic sarcoplasmic reticulum (SR) calcium leak and subsequent muscle weakness in aged nematodes and 2) mitochondrial ROS oxidizes nearby UNC-68 channels and exacerbates SR calcium leak in body wall muscle. Aim One will test whether leaky UNC-68 channels play a role in C. elegans muscle weakness. We first established that UNC-68 remodeling increases with age in WT worms, but is accelerated in FKB-2 KO worms using immunoprecipitation and immunoblot. We have determined that FKB-2 depletion results in reduced peak Ca2+ transients and blunted UNC-68 caffeine activation by crossing WT and FKB-2 KO worms with Pmyo-3: GCaMP2 worms. In Aim Two, we will assess the contribution of mitochondrial ROS in UNC-68 dysfunction by measuring mitochondrial free radicals in two electron transport chain (ETC) mutant strains, clk-1 and mev-1. We have found that the timing of UNC-68 remodeling correlates with their lifespan differences; clk-1 is long-lived and lacks UNC- 68 remodeling until old age, while mev-1 is short-lived and has remodeled UNC-68 channels earlier in life. Successful completion of the proposed studies will define the contributions of pathological SR calcium leak in age-dependent muscle function loss.