Reversing Skeletal Muscle Myopathy by Hydrogen Sulfide

硫化氢逆转骨骼肌肌病

• 批准号: 10557832
• 负责人: Suresh C. Tyagi
• 金额: $ 33.88万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557832
• 关键词: Angiography; Atrophic; Attenuated; Biological Assay; Birth; Body Weight; CRISPR/Cas technology; Cell Differentiation process; Cell Line; Cell Proliferation; Child; Chronic; Collagen; Cystathionine beta-Synthase; Cysteine Desulfhydrase; Data; Deposition; Deterioration; Diameter; Endothelial Cells; Enzymes; Exhibits; FOXO1A gene; Fatigue; GDF8 gene; Generations; Genes; Genetic Transcription; Goals; Heterozygote; Homocysteine; Homocystinuria; Hydrogen Sulfide; Hyperhomocysteinemia; Hypoxia; Image; Immunohistochemistry; Impairment; In Vitro; Ischemia; Isolated limb perfusion; Lasers; Ligation; Measures; Mediating; Metabolic; Modality; Mus; Muscle; Muscle Fibers; Muscular Atrophy; Mutation; Myopathy; Natural regeneration; Phosphorylation; Plasma; Predisposition; Proliferating; Proto-Oncogene Proteins c-akt; Roentgen Rays; Role; Signal Transduction; Signaling Molecule; Skeletal Muscle; Starvation; Teenagers; Testing; Therapeutic; Tissues; Transcript; Transduction Gene; Transgenic Mice; Transgenic Organisms; Vascular Endothelial Growth Factors; attenuation; density; design; femoral artery; frailty; hypoxia inducible factor 1; in vivo; knock-down; limb ischemia; muscle regeneration; novel; prevent; response; satellite cell; skeletal muscle wasting; small molecule; tissue oxygenation; vasculogenesis

Children born with severe homocystinuria due to homozygous cystathionine beta synthase deficiency (CBS-/-) exhibit poor body weights, skeletal muscle myopathy and die in teenage. Although mice with homozygous CBS mutation die shortly after birth, the heterozygous CBS-/+ survives. Our preliminary data suggests that enzymes, CBS and cystathionine gamma-lyase (CSE) that irreversibly remove homocysteine (Hcy) by converting to hydrogen sulfide (H2S), are decreased in skeletal muscle. Although lowering of Hcy levels and generation of H2S is beneficial, the mechanism by which HHcy causes of skeletal muscle wasting and frailty is unknown. The long-term goal of this project is to understand the mechanism of muscle wasting in HHcy and evaluate the potential beneficial effects of H2S signaling in reversing skeletal muscle wasting and myopathy. The central hypothesis of this proposal is that HHcy causes skeletal muscle deterioration by compromising vasculogenesis, by enhancing muscle atrophy and by limiting skeletal muscle regeneration and H2S reverses these changes. We will test this hypothesis by following three specific aims: Specific Aim #1: To determine whether the HHcy inhibits muscle specific AKT, HIF-1, and AMPK signaling and impairs vasculogenesis and H2S reverses impaired vasculogenesis. Specific Aim #2: To determine whether the HHcy attenuates PGC-1 signaling and instigates atrogene expression and causes muscular atrophy and H2S mitigates muscle atrophy. Specific Aim #3: To determine whether the HHcy enhances TGF-1 signaling and myostatin levels, thereby suppresses muscle regeneration and H2S ameliorates these changes.

由纯合性胱硫醚β合酶缺乏症(CBS-/-)引起的严重同型半胱氨酸尿症 表现出体重不足，骨骼肌病，并在十几岁时死亡。尽管CBS纯合子小鼠 突变在出生后不久就会死亡，杂合子CBS-/+存活下来。我们的初步数据表明 酶、CBS和半胱硫氨酸伽马裂解酶(CSE)通过以下途径不可逆地清除同型半胱氨酸(Hcy) 转化为硫化氢(H_2S)，在骨骼肌中减少。虽然同型半胱氨酸水平和 硫化氢的产生是有益的，HHcy导致骨骼肌萎缩和虚弱的机制是 未知。该项目的长期目标是了解HHcy和HHcy患者肌肉萎缩的机制。 评估硫化氢信号在逆转骨骼肌萎缩和肌病方面的潜在有益作用。 这一建议的中心假设是HHcy通过以下方式导致骨骼肌退化 通过加强肌肉萎缩和限制骨骼肌而影响血管生成 再生和硫化氢逆转了这些变化。我们将通过以下三个具体目标来验证这一假设： 特定目标#1：确定HHcy是否抑制肌肉特异性AKT、HIF-1和AMPK 信号转导并损害血管生成，而硫化氢逆转受损的血管生成。 特定目标#2：确定HHcy是否减弱PGC-1信号并刺激萎缩 表达并导致肌肉萎缩，而硫化氢可以缓解肌肉萎缩。 具体目标#3：确定同型半胱氨酸是否增强转化生长因子-1信号和肌肉生长抑素水平 从而抑制肌肉再生，而硫化氢改善这些变化。

项目成果

Gut microbiota and the periodontal disease: role of hyperhomocysteinemia.

• DOI: 10.1139/cjpp-2020-0215
• 发表时间: 2020-07
• 期刊: Canadian journal of physiology and pharmacology
• 影响因子: 2.1
• 作者: Dragana Stanisic;M. Jovanović;Akash K. George;R. Homme;N. Tyagi;S. Tyagi;Mahavir Singh

Simulation of COVID-19 symptoms in a genetically engineered mouse model: implications for the long haulers.

• DOI: 10.1007/s11010-022-04487-0
• 发表时间: 2023-01
• 期刊: Molecular and cellular biochemistry
• 影响因子: 4.3