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Muscle GPRC6A regulation of protein turnover with overload and disuse recovery

肌肉 GPRC6A 对过载和废用恢复中蛋白质周转的调节

基本信息

批准号：
10625420
负责人：
James A Carson
金额：
$ 16.94万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625420
关键词：
Acceleration Activities of Daily Living Adult Area Arginine Atrophic Attenuated Biology Clinical Communication Culture Media Disuse Atrophy Exercise Fatty Liver Female Foundations G-Protein-Coupled Receptors GPRC6A gene GTP-Binding Proteins Genetic Glucose Intolerance Goals Growth Growth Factor Health High Fat Diet Hindlimb Suspension Homeostasis Hospitalization Human Immobilization In Vitro Inflammation Insulin Insulin Resistance Interleukin-6 Intervention Investigation Knockout Mice Knowledge Ligands Link Maintenance Mechanics Metabolic Metabolic hormone Metabolic syndrome Metabolism Modeling Molecular Mus Muscle Muscle Fibers Muscle Proteins Muscular Atrophy Obesity Organ Osteocalcin Pathway interactions Patients Peptides Peripheral Pharmacologic Substance Population Process Property Proteins Publishing Recovery Regulation Research Role Serum Signal Transduction Skeletal Muscle Stretching Testing Testosterone Tissues autocrine cell type cytokine fibroblast growth factor 21 glucagon-like peptide 1 glucose tolerance improved in vitro Model in vivo insulin sensitivity link protein male muscle form muscle metabolism new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics paracrine pharmacologic pre-clinical prevent protein degradation receptor reduced muscle mass response sedentary lifestyle skeletal muscle wasting synergism therapeutic target

项目摘要

Skeletal muscle mass maintenance is critical for metabolic health and functional capacity and becomes a challenge during forced immobility or sedentary behavior. Despite progress in understanding the molecular drivers of load-induced muscle growth, there remains a need for novel approaches and different mechanistic paradigms to enhance muscle recovery from atrophy. Although load-induced muscle growth and recovery from disuse muscle atrophy involve protein accretion, the growth processes differ in the extent of the remodeling, damage, and inflammation present. We will mechanistically investigate a novel regulatory paradigm involved in skeletal muscle mass and metabolism regulation to improve our understanding of recovery from disuse atrophy and identify therapeutic targets for treating low muscle mass in patients. GPRC6A is a G-protein-linked receptor expressed in many tissues, including skeletal muscle, and has multiple ligands, including the peptide osteocalcin. Ligand activation of GPRC6A improves glucose tolerance and peripheral insulin sensitivity and prevents high-fat diet-induced hepatosteatosis in mice. GPRC6A knockout mice manifest metabolic syndrome, loss of muscle mass, glucose intolerance, and insulin resistance. There is evidence that signaling initiated by the skeletal muscle GPRC6A receptor can regulate muscle growth and metabolism. However, skeletal muscle GPRC6A's role in disuse atrophy and recovery is not known. Our investigative team’s synergistic expertise in GPRC6A function, metabolism, in vitro myotube growth, in vivo preclinical disuse and recovery models, and muscle biology provides a unique opportunity to study this novel regulatory paradigm. Our project's expected results hold substantial potential for identifying therapeutic targets to benefit muscle accretion in low muscle mass patients. The proposed study will provide foundational evidence for novel therapeutic paradigms to improve skeletal muscle load sensitivity linked to disuse atrophy and recovery. Genetic and pharmacological approaches will investigate GPRC6A regulation of muscle mass accretion and contractile function. Our central hypothesis is that loss of skeletal muscle GPRC6A signaling will attenuate recovery from disuse atrophy in male and female mice. Furthermore, GPRC6A activation by Ocn will accelerate the recovery of mass, metabolic properties, and contractile function. Aim 1 will investigate muscle GPRC6A’s role in myotube growth and atrophy in vitro. Established models of high serum media and stretch-induced growth in additional to stretch-release to examine myotube atrophy will be used to assess effects on stretch and serum-induced growth. Aim 2 will evaluate the role of GPRC6A signaling in disuse atrophy and the load-induced recovery of muscle mass and contractile and metabolic function in vivo. Normal cage ambulation after hindlimb suspension-induced disuse will examine recovery from atrophy. Our results will provide the foundation for novel therapeutic approaches that activate GPRC6A via ligands such as testosterone or other pharmaceutical interventions.

骨骼肌质量的维持对代谢健康和功能能力至关重要，在强迫不动或久坐不动的行为中的挑战。尽管在了解分子生物学方面取得了进展，尽管负荷诱导的肌肉生长的驱动因素，仍然需要新的方法和不同的机制，范例，以增强肌肉从萎缩中恢复。虽然负荷引起的肌肉生长和恢复，废用性肌肉萎缩涉及蛋白质增加，生长过程在重塑的程度上不同，损伤和炎症。我们将机械地研究一种新的监管范式，骨骼肌质量和代谢调节，以提高我们对废用性萎缩恢复的理解并确定用于治疗患者低肌肉质量的治疗靶点。GPRC6A是一个G蛋白连接的受体在包括骨骼肌在内的许多组织中表达，并具有多种配体，包括肽骨钙素GPRC6A的配体活化改善葡萄糖耐量和外周胰岛素敏感性，预防高脂饮食诱导的小鼠脂肪肝。GPRC6A敲除小鼠表现出代谢综合征，肌肉质量损失、葡萄糖耐受不良和胰岛素抵抗。有证据表明，信号启动由骨骼肌GPRC6A受体可调节肌肉生长和代谢。然而，骨骼肌 GPRC6A在废用性萎缩和恢复中的作用尚不清楚。我们的调查团队在以下方面的协同专业知识 GPRC6A功能、代谢、体外肌管生长、体内临床前废用和恢复模型，以及肌肉生物学提供了一个独特的机会来研究这种新的监管模式。我们的项目这些结果对于确定治疗靶点以在低肌生长中有益于肌肉生长具有很大的潜力。大量患者。这项拟议的研究将为新的治疗范例提供基础证据，改善与废用性萎缩和恢复相关骨骼肌负荷敏感性。遗传和药理学方法将研究GPRC6A对肌肉质量增加和收缩功能的调节。我们的中央假设骨骼肌GPRC6A信号传导的丧失将减弱从废用性萎缩中的恢复，雄性和雌性小鼠。此外，Ocn激活GPRC6A将加速质量恢复，代谢特性和收缩功能。目的1研究GPRC6A在肌管生长中的作用和体外萎缩。建立了高血清培养基和拉伸诱导生长的模型，拉伸释放检查肌管萎缩将用于评估对拉伸和血清诱导的肌管萎缩的影响。增长目的2将评估GPRC6A信号在废用性萎缩和负荷诱导的恢复中的作用。肌肉质量以及体内的收缩和代谢功能。后肢后正常笼状肌悬浮诱导的废用将检查从萎缩的恢复。我们的研究结果将为通过配体如睾酮或其它药物来激活GPRC6A的新的治疗方法干预措施。