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：
10463302
负责人：
James A Carson
金额：
$ 20.33万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10463302
关键词：
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 Protein alpha Subunits, Gs Genetic Glucose Intolerance Goals Growth Growth Factor Health High Fat Diet Hindlimb Suspension Homeostasis Hospitalization Human 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 Pharmacology 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 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.

骨骼肌质量维护对于代谢健康和功能能力至关重要，并成为在强制性固定或久坐行为中的挑战。尽管在理解分子方面取得了进展负载引起的肌肉生长的驱动因素仍需要新颖的方法和不同的机械范式增强肌肉恢复萎缩。尽管负载引起的肌肉生长和从废除肌肉萎缩涉及蛋白质积聚，生长过程在重塑的程度上有所不同，损害和炎症。我们将机械地研究与骨骼肌质量和新陈代谢调节，以提高我们对失去萎缩恢复的理解并确定治疗患者低肌肉的治疗靶标。 GPRC6A是G蛋白连接的受体在许多组织中表达，包括骨骼肌，并具有多个配体，包括辣椒骨钙素。 GPRC6A的配体激活可提高葡萄糖耐受性和周围胰岛素敏感性和防止高脂饮食引起的小鼠肝病。 GPRC6A淘汰小鼠明显代谢综合征，肌肉质量，葡萄糖耐药性和胰岛素抵抗的丧失。有证据表明发起的信号由骨骼肌GPRC6A受体可以调节肌肉生长和代谢。但是，骨骼肌 GPRC6A在废弃萎缩和恢复中的作用尚不清楚。我们的调查团队的协同专业知识 GPRC6A功能，代谢，体外肌管的生长，体内临床前解和恢复模型以及肌肉生物学为研究这种新型调节范式提供了独特的机会。我们的项目有望结果具有识别治疗靶标以使低肌肉肌肉积聚的巨大潜力大众患者。拟议的研究将为新的治疗范例提供基本证据改善与萎缩和恢复有关的骨骼肌肉负荷灵敏度。遗传和药理方法将研究GPRC6A肌肉质量积聚和收缩功能的调节。我们的中心假设是骨骼肌GPRC6A信号传导的丧失将减轻废弃萎缩的恢复雄性和雌鼠。此外，OCN激活GPRC6A将加速质量的恢复，代谢特性和收缩功能。 AIM 1将研究肌肉GPRC6A在Myotube增长中的作用和体外萎缩。建立的高血清培养基模型和拉伸引起的增长检查肌管萎缩的拉伸释放将用于评估对拉伸和血清诱导的影响生长。 AIM 2将评估GPRC6A信号传导在废弃萎缩中的作用和负载引起的恢复肌肉质量和收缩和代谢功能在体内。后肢的正常笼子救护悬浮诱导的废物将检查从萎缩中的恢复。我们的结果将为新型热方法通过睾丸激素或其他药物的配体激活GPRC6A 干预措施。