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

• 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
• 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

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.

骨骼肌质量维持对于代谢健康和功能能力至关重要，并成为 强迫不动或久坐行为期间的挑战。尽管对分子的理解取得了进展 作为负载引起的肌肉生长的驱动因素，仍然需要新的方法和不同的机制 增强肌肉从萎缩中恢复的范例。尽管负荷引起的肌肉生长和恢复 废用性肌肉萎缩涉及蛋白质积累，生长过程因重塑程度而异， 存在损伤和炎症。我们将机械地研究一种新的监管范式，涉及 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 并确定治疗低肌肉质量患者的治疗目标。 GPRC6A 是一种 G 蛋白连接的 受体在许多组织中表达，包括骨骼肌，并具有多种配体，包括肽 骨钙素。 GPRC6A 的配体激活可改善葡萄糖耐量和外周胰岛素敏感性 预防高脂肪饮食引起的小鼠肝脂肪变性。 GPRC6A基因敲除小鼠表现出代谢综合征， 肌肉质量损失、葡萄糖不耐受和胰岛素抵抗。有证据表明，信号由 骨骼肌GPRC6A受体可以调节肌肉的生长和代谢。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具有协同专业知识 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 肌肉生物学为研究这种新颖的调控范式提供了独特的机会。我们的项目预期 结果对于确定有利于低肌肉增长的治疗靶点具有巨大的潜力 大量患者。拟议的研究将为新的治疗范例提供基础证据 提高与废用性萎缩和恢复相关的骨骼肌负荷敏感性。遗传和药理学 这些方法将研究 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 信号传导的丧失会减弱废用性萎缩的恢复 雄性和雌性小鼠。此外，Ocn 激活 GPRC6A 将加速质量的恢复， 代谢特性和收缩功能。目标 1 将研究肌肉 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影响 生长。目标 2 将评估 GPRC6A 信号传导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。后肢正常笼内行走 暂停引起的废用将检查萎缩的恢复情况。我们的结果将为 通过睾酮或其他药物等配体激活 GPRC6A 的新治疗方法 干预措施。