Reversing Skeletal Muscle Myopathy by Hydrogen Sulfide

由于纯合型胱硫醚β合酶缺乏症（CBS-/-）而患有严重同型胱氨酸尿症的儿童 表现出体重不足、骨骼肌肌病并在青少年时期死亡。尽管携带纯合子CBS的小鼠 突变在出生后不久死亡，杂合子CBS-/+存活。我们的初步数据显示， 酶，CBS和胱硫醚γ-裂解酶（CSE），通过 转化为硫化氢（H2S），在骨骼肌中减少。虽然降低Hcy水平， H2S的产生是有益的，HHcy导致骨骼肌消耗和脆弱的机制是 未知本项目的长期目标是了解高同型半胱氨酸引起肌肉萎缩的机制， 评估H2S信号在逆转骨骼肌萎缩和肌病中的潜在有益作用。 该建议的中心假设是，HHcy通过以下方式引起骨骼肌退化： 通过促进肌肉萎缩和限制骨骼肌， 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： 具体目标#1：确定HHcy是否抑制肌肉特异性AKT、HIF-1和AMPK 信号传导并损害血管发生，H2S逆转受损的血管发生。 具体目标#2：确定HHcy是否减弱PGC-1信号传导并刺激萎缩性细胞因子 H2S表达并引起肌肉萎缩，H2S减轻肌肉萎缩。 具体目标#3：为了确定HHcy是否增强TGF-β 1信号传导和肌肉生长抑制素水平， 从而抑制肌肉再生，H2S改善这些变化。

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.