Regulation of macrophage metabolism in aged muscle during recovery

衰老肌肉恢复过程中巨噬细胞代谢的调节

• 批准号: 10622569
• 负责人: Micah J Drummond
• 金额: $ 62.23万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622569
• 关键词: Acceleration; Adopted; Aging; Anti-Inflammatory Agents; Attenuated; Automobile Driving; Bone Marrow; Bone Marrow Cell Transplantation; Bone Marrow Cells; Bone Marrow Transplantation; Cell physiology; Cells; Characteristics; Chemicals; Citric Acid Cycle; Classification; Coupled; Data; Defect; Development; Disuse Atrophy; Elderly; Enzymes; Event; Exhibits; Fibrosis; Functional disorder; Future; Genetic; Genetic Transcription; Glycolysis; Growth; Growth Factor; Health; Hematopoietic; Hindlimb Suspension; Human; Immobilization; Immune system; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; Interruption; Invaded; Knowledge; Limb structure; Literature; Macrophage; Macrophage Activation; Mediating; Metabolic; Metabolic Diseases; Metabolism; Methodology; Mus; Muscle; Muscle satellite cell; Operative Surgical Procedures; Oxidative Phosphorylation; Phenotype; Recovery; Recovery Support; Regulation; Resolution; Rodent; Role; Serum; Skeletal Muscle; Stimulus; Succinates; Testing; Therapeutic; Transcript; Translating; age related; aged; bone aging; cytokine; disability; experimental study; extracellular; fall risk; falls; hypoxia inducible factor 1; in vivo; mitochondrial dysfunction; mouse genetics; mouse model; muscle aging; muscle regeneration; novel; pre-clinical; precursor cell; prevent; programs; reduced muscle mass; response; restoration; sarcopenia; single-cell RNA sequencing; stem; stem cell function; therapeutic development; transcription factor; transcriptome; young adult

Abstract Muscle regrowth and function following disuse atrophy in aged muscle is significantly compromised, and this increases the risk for falls, long-term disability and loss of independence. Therapeutic strategies to enhance muscle recovery are non-existent stemming from a poor understanding of cellular mechanism during regrowth in aging muscle. Invasion of muscle macrophages and polarization to pro- and anti-inflammatory states are critical to promote muscle stem cell function and the full resolution of muscle and function following disuse. More recently, macrophage metabolism has been shown to be tightly coupled to the inflammatory state of activated macrophages and regulated by transcription factors such as HIF-1α and accumulation of TCA intermediates such as succinate. Our preliminary data in impaired aged muscle during early recovery supports decreased macrophage succinate and HIF-1α corresponding to a reduced macrophage glycolytic and inflammatory program and functional characteristics. Therefore, using novel mouse genetic and bone marrow transfer experiments, along with chemical approaches and in vitro studies, we will test if succinate and HIF-1α are key regulatory steps for macrophage metabolic and inflammatory activation during regrowth from disuse in aging muscle and if this dysfunction arises from an aged immune system. In Aim 2, we will translate our pre-clinical findings to young and older humans and confirm our hypothesis by extensively characterizing muscle macrophage metabolic and inflammatory functional states in vivo and in vitro during recovery from disuse atrophy. We anticipate that the findings will identify macrophage metabolism as a future target to accelerate the recovery of aged muscle following disuse related events (e.g., surgery, illness).

摘要