a Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
b Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Can J Physiol Pharmacol. 2019 Jun;97(6):441-456. doi: 10.1139/cjpp-2018-0501. Epub 2018 Nov 13.
Elevated homocysteine (Hcy), i.e., hyperhomocysteinemia (HHcy), causes skeletal muscle myopathy. Among many cellular and metabolic alterations caused by HHcy, oxidative and endoplasmic reticulum (ER) stress are considered the major ones; however, the precise molecular mechanism(s) in this process is unclear. Nevertheless, there is no treatment option available to treat HHcy-mediated muscle injury. Hydrogen sulfide (HS) is increasingly recognized as a potent anti-oxidant, anti-apoptotic/necrotic/pyroptotic, and anti-inflammatory compound and also has been shown to improve angiogenesis during ischemic injury. Patients with CBS mutation produce less HS, making them vulnerable to Hcy-mediated cellular damage. Many studies have reported bidirectional regulation of ER stress in apoptosis through JNK activation and concomitant attenuation of cell proliferation and protein synthesis via PI3K/AKT axis. Whether HS mitigates these detrimental effects of HHcy on muscle remains unexplored. In this review, we discuss molecular mechanisms of HHcy-mediated oxidative/ER stress responses, apoptosis, angiogenesis, and atrophic changes in skeletal muscle and how HS can restore skeletal muscle homeostasis during HHcy condition. This review also highlights the molecular mechanisms on how HS could be developed as a clinically relevant therapeutic option for chronic conditions that are aggravated by HHcy.
高同型半胱氨酸（Hcy），即高同型半胱氨酸血症（HHcy），可导致骨骼肌肌病。在 HHcy 引起的许多细胞和代谢改变中，氧化应激和内质网（ER）应激被认为是主要的改变；然而，这一过程的确切分子机制尚不清楚。尽管如此，目前尚无治疗 HHcy 介导的肌肉损伤的方法。硫化氢（HS）作为一种有效的抗氧化剂、抗细胞凋亡/坏死/焦亡和抗炎化合物，其作用正得到越来越多的认可，并且已被证明可改善缺血性损伤期间的血管生成。CBS 基因突变的患者产生的 HS 较少，使他们容易受到 Hcy 介导的细胞损伤。许多研究报告称，通过 JNK 激活， ER 应激在细胞凋亡中存在双向调节作用，同时通过 PI3K/AKT 轴抑制细胞增殖和蛋白质合成。HS 是否能减轻 HHcy 对肌肉的这些有害影响仍有待探索。在这篇综述中，我们讨论了 HHcy 介导的氧化/ER 应激反应、细胞凋亡、血管生成和骨骼肌萎缩变化的分子机制，以及 HS 如何在 HHcy 状态下恢复骨骼肌的稳态。这篇综述还强调了如何将 HS 开发为一种有临床意义的治疗选择，用于因 HHcy 加重的慢性疾病的分子机制。
