Coordinated mechanisms to rescue bioenergetics and sarcopenia in aging

拯救衰老过程中生物能学和肌肉减少症的协调机制

基本信息

  • 批准号:
    10672292
  • 负责人:
  • 金额:
    $ 32.62万
  • 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:
    2022-08-01 至 2027-04-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY A widely conserved hallmark of aging is the decline in muscle mass and strength, promoting frailty, loss of independence and disability. Crucial for this is our gap in knowledge regarding mechanisms linking bioenergetic stimulation to muscle anabolism. Glucocorticoid steroids have pervasive effects on energy metabolism and muscle function. Dosing intermittence appears crucial to the benefits/risks ratio of these drugs in dystrophic animal models and patients, i.e. in genetic myopathies. Here we investigate whether intermittent glucocorticoids increase performance in aged muscle, where weakness and sarcopenia are not dependent on specific genetic insults. Our new results in 24 months-old WT mice show that a chronic regimen of intermittent once-weekly prednisone increased muscle performance in aging mice to levels comparable to young adult mice (4 months- old). Remarkably, treatment rescued both mitochondrial respiration and muscle mass in aging mice to young- like levels. Mechanistically, we found that bioenergetic, functional and anabolic effects of intermittent prednisone were blunted upon inducible ablation of PGC1a in adult muscle. While the role of PGC1a in boosting mitochondrial capacity in aged muscle is more established, its effects on age-related sarcopenia and weakness are still debated with conflicting results from constitutive knockout or overexpression models. Scattered reports have hinted at a role of PGC1a in activating growth pathways, including biosynthesis of amino acids like alanine, but this is still largely unknown in muscle aging. Here we will investigate the mechanisms through which a bioenergetic stimulation like intermittent prednisone rescues both oxidative metabolism and mass gain in muscle aging. In Aim 1, we will determine the extent to which intermittence discriminates deleterious versus beneficial effects of glucocorticoids in aging muscle. We hypothesize that dosing intermittence shifts exogenous glucocorticoid effects from a PGC1a-lowering pro-wasting program to a PGC1a-dependent pro-ergogenic program, i.e. balanced gain of performance and mass. We will test this through inducible muscle-specific PGC1a ablation after natural aging. In Aim 2 we will establish the role of muscle Lipin1 in PGC1a re-activation in muscle aging. We hypothesize that Lipin1 supports mitochondrial function in muscle aging and mediates the PGC1a re- activation in response to intermittent glucocorticoids. To test this, we will use our newly derived mice with muscle- restricted inducible Lipin1 ablation after natural aging. In Aim 3, we will elucidate the extent to which bioenergetics rescue sarcopenia in aging through amino acid biosynthesis. We hypothesize that mitochondrial reactivation fuels amino acid biogenesis, supporting protein synthesis during muscle aging. We will test this by tracing glucose-derived carbons into amino acids in oxidative versus glycolytic myofibers. We will also test the extent to which muscle PGC1a mediates these effects in young versus aging muscle. In summary, here we leverage the unprecedented effects of intermittent glucocorticoids to discern unrecognized mechanisms of aging physiology and rejuvenate muscle bioenergetics and anabolism.
项目总结

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)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Mattia Quattrocelli其他文献

Mattia Quattrocelli的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Mattia Quattrocelli', 18)}}的其他基金

Harnessing novel glucocorticoid biology to treat diabetic cardiomyopathy
利用新型糖皮质激素生物学治疗糖尿病心肌病
  • 批准号:
    10733533
  • 财政年份:
    2023
  • 资助金额:
    $ 32.62万
  • 项目类别:
ROLE OF CIRCADIAN RHYTHM AND INTERMITTENT DOSING IN MUSCLE TRIGLYCERIDE LIPASE INDUCTION BY GLUCOCORTICOIDS
昼夜节律和间歇给药在糖皮质激素诱导肌肉甘油三酯脂肪酶中的作用
  • 批准号:
    10657826
  • 财政年份:
    2022
  • 资助金额:
    $ 32.62万
  • 项目类别:
ROLE OF CIRCADIAN RHYTHM AND INTERMITTENT DOSING IN MUSCLE TRIGLYCERIDE LIPASE INDUCTION BY GLUCOCORTICOIDS
昼夜节律和间歇给药在糖皮质激素诱导肌肉甘油三酯脂肪酶中的作用
  • 批准号:
    10518578
  • 财政年份:
    2022
  • 资助金额:
    $ 32.62万
  • 项目类别:
CHRONO-MECHANISMS of CARDIOMETABOLIC PHARMACOLOGY
心脏代谢药理学的时间机制
  • 批准号:
    10271560
  • 财政年份:
    2021
  • 资助金额:
    $ 32.62万
  • 项目类别:
Glucocorticoid and circadian clock coregulation of insulin sensitivity and metabolism
糖皮质激素和生物钟共同调节胰岛素敏感性和代谢
  • 批准号:
    10191173
  • 财政年份:
    2019
  • 资助金额:
    $ 32.62万
  • 项目类别:
Glucocorticoid and circadian clock coregulation of insulin sensitivity and metabolism
糖皮质激素和生物钟共同调节胰岛素敏感性和代谢
  • 批准号:
    10166838
  • 财政年份:
    2019
  • 资助金额:
    $ 32.62万
  • 项目类别:
Glucocorticoid and circadian clock coregulation of insulin sensitivity and metabolism
糖皮质激素和生物钟共同调节胰岛素敏感性和代谢
  • 批准号:
    9806667
  • 财政年份:
    2019
  • 资助金额:
    $ 32.62万
  • 项目类别:

相似海外基金

Investigating HDAC3 phosphorylation as an epigenetic regulator of memory formation in the adult and aging brain
研究 HDAC3 磷酸化作为成人和衰老大脑记忆形成的表观遗传调节剂
  • 批准号:
    10752404
  • 财政年份:
    2023
  • 资助金额:
    $ 32.62万
  • 项目类别:
The Health of Aging Parents of Adult Children with Serious Conditions
患有严重疾病的成年子女的年迈父母的健康
  • 批准号:
    10660046
  • 财政年份:
    2023
  • 资助金额:
    $ 32.62万
  • 项目类别:
Understanding Longer-Living Older Adult Research: The Summer Program on Aging
了解长寿老年人研究:老龄化夏季项目
  • 批准号:
    476343
  • 财政年份:
    2022
  • 资助金额:
    $ 32.62万
  • 项目类别:
Role of sensory experience in the regulation of plasticity in the developing, adult and aging brain
感官体验在发育、成人和衰老大脑可塑性调节中的作用
  • 批准号:
    RGPIN-2019-04761
  • 财政年份:
    2022
  • 资助金额:
    $ 32.62万
  • 项目类别:
    Discovery Grants Program - Individual
Adult Cognitive and Neurobiological Indicators of Aging: Impact of Adversity and Social Support
成人衰老的认知和神经生物学指标:逆境和社会支持的影响
  • 批准号:
    10365348
  • 财政年份:
    2022
  • 资助金额:
    $ 32.62万
  • 项目类别:
Adult Cognitive and Neurobiological Indicators of Aging: Impact of Adversity and Social Support
成人衰老的认知和神经生物学指标:逆境和社会支持的影响
  • 批准号:
    10700796
  • 财政年份:
    2022
  • 资助金额:
    $ 32.62万
  • 项目类别:
Endogenous barcoding to determine complex dynamics of adult neurogenesis in aging and Alzheimer's disease
内源条形码确定衰老和阿尔茨海默病中成人神经发生的复杂动态
  • 批准号:
    10651861
  • 财政年份:
    2022
  • 资助金额:
    $ 32.62万
  • 项目类别:
Investigating the interface of epigenetics and metabolism underlying memory formation in the adult, aging, and AD brain
研究成人、衰老和 AD 大脑中记忆形成的表观遗传学和代谢界面
  • 批准号:
    10420533
  • 财政年份:
    2022
  • 资助金额:
    $ 32.62万
  • 项目类别:
Endogenous barcoding to determine complex dynamics of adult neurogenesis in aging and Alzheimer's disease
内源条形码确定衰老和阿尔茨海默病中成人神经发生的复杂动态
  • 批准号:
    10846200
  • 财政年份:
    2022
  • 资助金额:
    $ 32.62万
  • 项目类别:
THE DEVELOPMENT OF MECHANISM-BASED ADULT STEM CELL TREATMENTS TO COMBAT AGING PATHOLOGIES
开发基于机制的成人干细胞疗法来对抗衰老病理学
  • 批准号:
    10721544
  • 财政年份:
    2022
  • 资助金额:
    $ 32.62万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了