Guangdong Yang*
*School of Surveying Geospatial Engineering, Syria
Correspondence: Guangdong Yang, School of Surveying Geospatial Engineering, Syria email: gyang2@tishreen.edu.sy
Received: 24 Feb, 2026; Accepted date: 09 Mar, 2026; Published date: 24 Mar, 2026
Citation: Guangdong Yang. “Building Muscles: The Molecular Regulation of Muscle Regeneration by Hydrogen Sulfide (H₂S).” J Aesthetic Surg Med (2025):111 DOI: 10.59462/ JASM.3.1.111
Copyright: © 2026 Guangdong Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Abstract
Hydrogen sulfide (H₂S) was originally considered toxic at elevated levels; however, over the past decade it has emerged as an important gasotransmitter alongside Nitric oxide and Carbon monoxide. H₂S is generated endogenously from L-cysteine by several enzymes and regulates diverse cellular and pathophysiological processes. Many of its biological effects are mediated through S-sulfhydration of cysteine residues on target proteins, altering enzymatic activity, protein stability, localization, and molecular interactions. Rapid growth in H₂S research reflects its expanding importance in biology and medicine. Given its critical role in health and disease, understanding H₂S metabolism and molecular signaling mechanisms may facilitate the development of novel therapeutic strategies. Recent findings indicate that H₂S plays an essential role in myogenesis and skeletal muscle regeneration following injury, suggesting potential applications in preventing age-related sarcopenia and treating muscle damage.
Introduction
Skeletal muscle is a highly plastic tissue capable of regeneration in response to injury, exercise, and disease. This regenerative capacity depends on tightly coordinated molecular signaling pathways that regulate satellite cell activation, proliferation, differentiation, and fusion [1,2]. Dysregulation of these processes contributes to muscle-wasting conditions such as sarcopenia, cachexia, and muscular dystrophy [3].
Gasotransmitters—small gaseous signaling molecules—have emerged as key modulators of muscle physiology. Among these, H₂S has gained attention as the third major endogenous gasotransmitter after nitric oxide (NO) and carbon monoxide (CO) [4,5]. Once considered merely a toxic environmental gas, H₂S is now recognized as a critical regulator of redox balance, mitochondrial function, inflammation, and cellular metabolism [6].
This mini-review summarizes current knowledge on H₂S biosynthesis, molecular mechanisms of action, and its emerging role in skeletal muscle regeneration and repair.
Biosynthesis and Metabolism of H₂S
Endogenous H₂S is synthesized primarily from L-cysteine through the enzymatic actions of cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) [7,8]. These enzymes exhibit tissue-specific expression patterns and contribute to finely tuned regulation of H₂S levels.
H₂S metabolism is tightly controlled by mitochondrial oxidation pathways, ensuring physiological concentrations are maintained [9]. Dysregulation of H₂S production or clearance has been implicated in cardiovascular, neurological, and metabolic diseases [10].
In skeletal muscle, CSE and 3-MST are particularly relevant, suggesting localized control of H₂S production during muscle repair [11].
Molecular Mechanisms of H₂S Signaling
S-Sulfhydration
A primary mechanism of H₂S signaling involves S-sulfhydration (also termed persulfidation), a post-translational modification in which a sulfur atom is added to cysteine residues on target proteins [12]. This modification alters protein conformation, enzymatic activity, and interaction networks.
S-sulfhydration has been shown to regulate key signaling molecules involved in oxidative stress responses and cytoskeletal organization [13].
Redox Regulation and Mitochondrial Function
H₂S plays a dual role in redox biology. At physiological concentrations, it acts as an antioxidant by enhancing glutathione levels and activating nuclear factor erythroid 2–related factor 2 (Nrf2) pathways [14]. It also modulates mitochondrial respiration by interacting with electron transport chain components [15].
Given that mitochondrial health is critical for muscle regeneration, these effects position H₂S as an important metabolic regulator during myogenesis.
Interaction with Other Gasotransmitters
H₂S signaling interacts with nitric oxide pathways, influencing vascular tone and perfusion in skeletal muscle [16]. Cross-talk between H₂S and NO may enhance angiogenesis and nutrient delivery during muscle repair [17].
Role of H₂S in Myogenesis and Muscle Regeneration
Satellite Cell Activation and Differentiation
Satellite cells are skeletal muscle stem cells responsible for regeneration [2]. Emerging evidence suggests that H₂S promotes satellite cell proliferation and differentiation by modulating key transcription factors such as MyoD and myogenin [18].
Experimental models indicate that inhibition of H₂S-producing enzymes impairs muscle regeneration, whereas H₂S donors enhance myogenic differentiation [19].
Anti-inflammatory Effects
Muscle injury triggers inflammatory responses that are essential for regeneration but detrimental when excessive. H₂S exhibits anti-inflammatory properties by suppressing pro-inflammatory cytokines and modulating NF-κB signaling [20]. These effects contribute to a favorable microenvironment for muscle repair.
Protection Against Muscle Atrophy and Sarcopenia
Age-related sarcopenia is characterized by reduced muscle mass and function. Declining H₂S production has been associated with aging tissues [21]. Preclinical studies suggest that H₂S supplementation may counteract oxidative stress and mitochondrial dysfunction in aging muscle, positioning it as a candidate therapeutic strategy.
Therapeutic Potential and Clinical Implications
The therapeutic application of H₂S relies on controlled delivery systems, as excessive levels can be cytotoxic. Slow-releasing H₂S donors and hybrid compounds are being developed to achieve physiological effects without toxicity [6].
In muscle injury models, H₂S donors have demonstrated improved regeneration and reduced fibrosis [19]. These findings suggest potential clinical applications in:
However, further translational and clinical studies are necessary to determine optimal dosing, timing, and safety.
Conclusion
Hydrogen sulfide has evolved from being considered a toxic gas to a recognized endogenous signaling molecule with profound biological effects. Through mechanisms such as S-sulfhydration, redox regulation, mitochondrial modulation, and anti-inflammatory signaling, H₂S plays a critical role in skeletal muscle regeneration. Emerging evidence supports its involvement in satellite cell activation and protection against muscle degeneration.
A deeper understanding of H₂S metabolism and molecular targets may facilitate the development of novel therapeutic strategies aimed at enhancing muscle regeneration and preventing age-related sarcopenia. Continued research will be essential to translate these promising findings into clinical practice.
References