Protective effect of exogenous hydrogen sulfide on diaphragm muscle fibrosis in streptozotocin-induced diabetic rats

Abstract

Diabetes mellitus has been shown to impair respiratory function. The diaphragm is an important skeletal muscle involved in respiration. Hydrogen sulfide (H2S) is one of the three endogenous gas messengers in mammals, which exhibits anti-fibrotic activity in some types of diabetes-related complications. However, whether and how H2S exerts its anti-fibrotic activity on the diabetic diaphragmatic muscle remains unclear. In this study, we explored the anti-fibrotic activity of exogenous H2S on the diaphragm using a streptozotocin (STZ)-induced diabetic rat model. The results showed that diaphragmatic biomechanical parameters were decreased, whereas the levels of inflammatory cytokines, collagen, and nucleotide-binding oligomerization domain-like receptor protein (NLRP) 3 inflammasome-related protein expression were increased in diabetic diaphragms. This implies that diabetes causes fibrosis of the diaphragm muscle through activation of NLRP3 inflammasome. After supplementation with exogenous H2S, the diaphragmatic biomechanical and pathological alterations were ameliorated and activation of NLRP3 inflammasome was inhibited, followed by a decline in diaphragm muscle inflammation and fibrosis. These results demonstrate for the first time that exogenous H2S effectively attenuates STZ-induced diabetic diaphragm muscle fibrosis, and that the underlying mechanism may be associated with suppression of the NLRP3 inflammasome-mediated inflammatory reaction. Impact statement Diabetes mellitus is a group of chronic metabolic disorders, which causes serious damage to a variety of organs, such as the retina, heart, and skeletal muscle. The diaphragm is an important skeletal muscle involved in respiration in mammals. Fibrosis of the diaphragm muscle affects its contractility, which in turn impairs respiratory function. Accumulating evidence suggests that exogenous hydrogen sulfide (H2S) exhibits anti-fibrotic activity in diabetes mellitus, but whether and how H2S exerts this anti-fibrotic effect in the diabetic diaphragm remains unclear. The current work for the first time reveals that exogenous H2S attenuates hyperglycemia-induced fibrosis of the diaphragm muscle and strengthens diaphragmatic biomechanical properties in diabetes mellitus, and the mechanism may involve the alleviation of collagen deposition by suppression of the nucleotide-binding oligomerization domain-like receptor protein (NLRP) 3 inflammasome-mediated inflammatory reaction. Therefore, H2S supplementation could be used as an efficient targeted therapy against the NLRP3 inflammasome in the diabetic diaphragm.

Hydrogen sulfide donor protects against mechanical ventilation‐induced atrophy and contractile dysfunction in the rat diaphragm

“… 22 Further, CysSSH is a nucleophile that can protect against oxidative stress in cells. 10 , 23 It is possible that exogenous H 2 S donors supplemented the endogenous H 2 S synthesis in diaphragm fibers during prolonged MV 24 , 25 ; this is a testable hypothesis worthy of future study. Clearly, future studies should investigate the specific role that CysSSH and other sulfur species play in protecting against VIDD.…”

Gasotransmitters: Potential Therapeutic Molecules of Fibrotic Diseases

“…Diabetes is related to the failure of multiple organs and can lead to respiratory dysfunction by reducing the endurance of respiratory muscles and lung capacity. The diaphragm is an important skeletal muscle in the mammalian breathing process [ 137 ]. Excessive inflammation of diabetes often leads to collagen deposition and muscle fibrosis.…”

“…Excessive inflammation of diabetes often leads to collagen deposition and muscle fibrosis. However, one recent study demonstrated that administration of NaHS could ameliorate hyperglycemia-induced diaphragm muscle fibrosis and improved the diaphragmatic biomechanical properties in diabetes mellitus, which might be associated with the alleviation of collagen deposition through the suppression of NLRP3 inflammasome-mediated inflammatory reaction [ 137 ]. This report confirmed that the therapeutic strategies aimed at inhibiting NLRP3 inflammasome-mediated fibrosis by utilizing exogenous H 2 S might serve as efficient targeted therapy in diabetes mellitus.…”

Cystathionine gamma‐lyase/H2S signaling facilitates myogenesis under aging and injury condition

“…43 H 2 S protects diaphragm muscle fibrosis and strengthens diaphragmatic biomechanical properties in streptozotocin-induced diabetic rats. 44 H 2 S also alleviates the injury of skeletal muscle in ischemia-reperfusion rats, improves muscle functions in high-fat-diet-fed mice, and increases muscle mass in db/db diabetic mice. 20,43,45,46 We and others recently discovered that H 2 S suppresses angiotensin II or hyperhomocysteinemia-induced skeletal muscle atrophy in mice via mitigation of endoplasmic reticulum stress and Golgi's stress response.…”

“…H 2 S induces the S ‐sulfhydration of Kv7 channel proteins and contributes to skeletal muscle hypercontractility in human malignant hyperthermia syndrome 43 . H 2 S protects diaphragm muscle fibrosis and strengthens diaphragmatic biomechanical properties in streptozotocin‐induced diabetic rats 44 . H 2 S also alleviates the injury of skeletal muscle in ischemia‐reperfusion rats, improves muscle functions in high‐fat‐diet‐fed mice, and increases muscle mass in db/db diabetic mice 20,43,45,46 .…”