Restoration of skeletal muscle homeostasis by hydrogen sulfide during hyperhomocysteinemia-mediated oxidative/ER stress condition

Abstract

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 (H2S) 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 H2S, 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 H2S 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 H2S can restore skeletal muscle homeostasis during HHcy condition. This review also highlights the molecular mechanisms on how H2S could be developed as a clinically relevant therapeutic option for chronic conditions that are aggravated by HHcy.

ROS systems are a new integrated network for sensing homeostasis and alarming stresses in organelle metabolic processes

“…Reactive oxygen species (ROS) are defined as oxygen-containing reactive species. It is well established that increased ROS play a vital role in promoting cardiovascular disease [ [1] , [2] , [3] ] such as hypertension, aortic aneurysm, hypercholesterolemia, atherosclerosis [ 4 ], diabetic vascular complication, cardiac ischemia reperfusion injury, myocardial infarction [ 5 ], heart failure, and cardiac arrhythmias [ 6 ], chronic kidney disease [ [7] , [8] , [9] , [10] , [11] ], hyperhomocysteinemia [ [12] , [13] , [14] ], metabolic syndrome [ 15 ], induction of regulatory T cells (Treg) and T cell-mediated inflammation [ 16 , 17 ], cigarette smoking [ 18 ], metabolically healthy obesity [ 19 , 20 ] and obesity [ 21 ], and tumorigenesis [ 22 ]. Additionally, ROS have been studied as the therapeutic targets for these disease progression and complications [ 23 ].…”

The role of cystatin C as a proteasome inhibitor in multiple myeloma

“…Hcy increases intracellular ROS by stimulating the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and integrin β 3 expression, ultimately upregulating osteoclast formation and activity [36]. Moreover, Hcy induces apoptosis in NF-κB activated primary human bone marrow stromal cells (BMSCs) and HS-5 cell line via the ROS-mediated mitochondrial pathway, which suggests the presence of an apoptotic effect on osteoblasts [35,37].…”

Imbalance of Homocysteine and H2S: Significance, Mechanisms, and Therapeutic Promise in Vascular Injury

“…The role of ER stress and the cross-talk between ER stress and oxidative stress in mediating endothelial dysfunction have been suggested in several pathological conditions including homocysteine exposure [62–65]. There are several lines of evidence suggesting that H 2 S could prevent homocysteine-induced ER stress [66–69], though these results were not derived from studies of vessels but from the skeletal muscle, neural system, and cardiomyocytes, it is very likely that the anti-ER stress capacity of H 2 S is also involved in its protective effect on vasculatures in hyperhomocysteinemic conditions, which however warrants further investigation.…”