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.

由于纯合胱淀粉β-合成酶缺乏（CBS - / - ）而出生的患有严重同叶尿尿症的儿童 表现出体重不佳，骨骼肌肌病和少年死亡。虽然纯合CBS的小鼠 突变在出生后不久死亡，杂合CBS - /+幸存。我们的初步数据表明 酶，CBS和胱淀粉γ-酯（CSE）通过不可逆地去除同型半胱氨酸（HCY） 转化为硫化氢（H2S），在骨骼肌中降低。虽然降低了HCY水平和 H2的产生是有益的，这是骨骼肌浪费和脆弱的HHCY原因的机制 未知。该项目的长期目标是了解HHCY和 评估H2S信号在反骨骼肌浪费和肌病中的潜在有益作用。 该提议的核心假设是HHCY通过 通过增强肌肉萎缩和限制骨骼肌肉来妥协血管发生 再生和H2S逆转了这些变化。我们将通过以下三个具体目标来检验这一假设： 特定目的＃1：确定HHCY是否抑制肌肉特异性AKT，HIF-1和AMPK 信号传导和损害血管生成，H2S逆转了血管生成受损。 特定目的＃2：确定HHCY是否会减弱PGC-1信号传导并促进阳性 表达并引起肌肉萎缩，H2S减轻肌肉萎缩。 特定目的＃3：确定HHCY是否增强了TGF-1信号传导和肌生抑素水平， 从而抑制肌肉再生，H2S可以改善这些变化。

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