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:
  • 金额:
    $ 16.94万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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James A Carson其他文献

James A Carson的其他文献

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{{ truncateString('James A Carson', 18)}}的其他基金

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
  • 财政年份:
    2022
  • 资助金额:
    $ 16.94万
  • 项目类别:
(PQ 12) The Regulation of Physical Function and Skeletal Muscle Metabolic Signaling After Cessation of 5-Fluorouracil Treatment
(PQ 12) 停止 5-氟尿嘧啶治疗后身体功能和骨骼肌代谢信号的调节
  • 批准号:
    9927604
  • 财政年份:
    2019
  • 资助金额:
    $ 16.94万
  • 项目类别:
Cachexia in ApcMin/+ mice: The role of IL-6
ApcMin/ 小鼠恶病质:IL-6 的作用
  • 批准号:
    9251557
  • 财政年份:
    2016
  • 资助金额:
    $ 16.94万
  • 项目类别:
GUT BARRIER DYSFUNCTION: THE TRIGGER FOR CACHEXIA IN APCMIN/+ MICE
肠道屏障功能障碍:APCMIN/小鼠恶病质的触发因素
  • 批准号:
    7959766
  • 财政年份:
    2009
  • 资助金额:
    $ 16.94万
  • 项目类别:
Cachexia in ApcMin/+ mice: The role of IL-6
ApcMin/ 小鼠恶病质:IL-6 的作用
  • 批准号:
    7790516
  • 财政年份:
    2008
  • 资助金额:
    $ 16.94万
  • 项目类别:
Cachexia in ApcMin/+ mice: The role of IL-6
ApcMin/ 小鼠恶病质:IL-6 的作用
  • 批准号:
    7466689
  • 财政年份:
    2008
  • 资助金额:
    $ 16.94万
  • 项目类别:
Cachexia in ApcMin/+ mice: The role of IL-6
ApcMin/ 小鼠恶病质:IL-6 的作用
  • 批准号:
    9228937
  • 财政年份:
    2008
  • 资助金额:
    $ 16.94万
  • 项目类别:
Cachexia in ApcMin/+ mice: The role of IL-6
ApcMin/ 小鼠恶病质:IL-6 的作用
  • 批准号:
    8695594
  • 财政年份:
    2008
  • 资助金额:
    $ 16.94万
  • 项目类别:
Cachexia in ApcMin/+ mice: The role of IL-6
ApcMin/ 小鼠恶病质:IL-6 的作用
  • 批准号:
    9432821
  • 财政年份:
    2008
  • 资助金额:
    $ 16.94万
  • 项目类别:
Cachexia in ApcMin/+ mice: The role of IL-6
ApcMin/ 小鼠恶病质:IL-6 的作用
  • 批准号:
    7619472
  • 财政年份:
    2008
  • 资助金额:
    $ 16.94万
  • 项目类别:

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