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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，并成为一种