CSE/H2S/SESN2 Signalling Mediates the Protective Effect of Exercise Against Immobilization-Induced Muscle Atrophy in Mice

IF 9.1 1区医学 Q1 GERIATRICS & GERONTOLOGY

Journal of Cachexia Sarcopenia and Muscle Pub Date : 2025-10-01 DOI:10.1002/jcsm.70083

Xiuru Li, Yating Huang, Xuege Yang, Sujuan Liu, Yanmei Niu, Li Fu

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Abstract

Background

Hydrogen sulphide (H₂S), a gasotransmitter synthesized by cystathionine-γ-lyase (CSE), exhibits antioxidant properties and may mimic exercise-induced muscle protection. However, its mechanistic role in muscle atrophy and exercise intervention remains unclear.

Methods

Six-month-old male wild-type (WT) and SESN2 knockout (SESN2^−/−) C57BL/6J mice were subjected to a 2-week hindlimb immobilization, followed by combined resistance and aerobic exercise or pharmacological intervention using the H₂S donor NaHS (30 μmol/kg) or the CSE inhibitor DL-propargylglycine (PAG, 50 mg/kg). In vitro, C₂C₁₂ myotubes were treated with H₂O₂ and NaHS to assess oxidative stress injury. Muscle mass, cross-sectional area (CSA), collagen deposition and oxidative stress markers were evaluated via histology, Western blot and immunofluorescence.

Results

Compared with the immobilization (IM) group, mice receiving a 2-week combined exercise intervention (IM + EX) exhibited significantly increased gastrocnemius muscle mass/body weight (10.86 ± 0.62 vs. 8.56 ± 1.61, p < 0.01), enlarged muscle fibre CSA (1628 ± 265 μm² vs. 905.5 ± 88.52 μm², p < 0.01) and reduced collagen deposition as indicated by Sirius red staining (collagen-positive area: 2.86% ± 1.12% vs. 7.06 ± 1.18%, p < 0.001). Pharmacological inhibition of CSE with PAG significantly attenuated these exercise-induced improvements (muscle mass/body weight: 10.22 ± 0.59, CSA: 1139 ± 96.21 μm², collagen area: 5.04 ± 0.66%, all p < 0.05 vs. IM + EX). Conversely, administration of the H₂S donor NaHS mimicked the protective effects of exercise, increasing muscle mass/body weight (8.94 ± 0.51), CSA (1474 ± 176.1 μm²) and reducing collagen accumulation (collagen area: 3.04 ± 0.74%, all p < 0.05 vs. IM). In vitro, NaHS treatment (30 μM) significantly reversed H₂O₂-induced reductions in myotube diameter (19.16 ± 0.91 μm vs. 15.61 ± 0.72 μm, p < 0.01) and improved fusion index (46.47 ± 1.51% vs. 35.28 ± 2.87%, p < 0.05). Western blot analysis showed that NaHS upregulated SESN2 and Nrf2 expression, as well as downstream antioxidant proteins HO-1 and NQO1 (p < 0.05), whereas SESN2 knockdown blocked these effects and abolished NaHS-mediated protection in myotubes. In SESN2^−/− mice, NaHS failed to increase muscle mass/body weight (7.24 ± 1.3 vs. WT + NaHS 10.12 ± 0.38, p < 0.001), CSA (699.2 ± 21.51 μm² vs. WT + NaHS 1189 ± 93.27 μm², p < 0.001) or antioxidant capacity, confirming the essential role of SESN2 in mediating H₂S-dependent muscle protection.

Conclusions

H₂S protects against disuse-induced muscle atrophy by enhancing antioxidant defences via the SESN2/Nrf2 signalling pathway. These findings identify H₂S as a potential exercise-mimetic therapeutic strategy for preserving muscle mass and function.

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CSE/H2S/SESN2信号介导运动对小鼠固定不动诱导的肌肉萎缩的保护作用

硫化氢（H2S）是一种由半胱硫氨酸-γ-裂解酶（CSE）合成的气体递质，具有抗氧化特性，可能模拟运动诱导的肌肉保护。然而，其在肌肉萎缩和运动干预中的机制作用尚不清楚。方法6月龄雄性野生型（WT）和SESN2基因敲除（SESN2-/-） C57BL/6J小鼠后肢固定2周，然后进行联合抵抗和有氧运动，或使用H2S供体NaHS （30 μmol/kg）或CSE抑制剂dl -丙基甘氨酸（PAG, 50 mg/kg）进行药物干预。体外用H2O2和NaHS处理C2C12肌管，评估氧化应激损伤。采用组织学、Western blot和免疫荧光法检测大鼠肌肉质量、横截面积（CSA）、胶原沉积和氧化应激指标。结果与固定化（IM）组相比，2周联合运动干预（IM + EX）组小鼠腓肠肌质量/体重显著增加（10.86±0.62比8.56±1.61,p < 0.01），肌纤维CSA增大（1628±265 μm2比905.5±88.52 μm2, p < 0.01），天狼星红染色显示胶原沉积减少（胶原阳性面积：2.86%±1.12%比7.06±1.18%,p < 0.001）。PAG对CSE的药理抑制显著减弱了这些运动诱导的改善（肌肉质量/体重：10.22±0.59,CSA: 1139±96.21 μm2，胶原面积：5.04±0.66%，与IM + EX相比均p < 0.05）。相反，H2S供体NaHS的保护作用与运动相似，增加肌肉质量/体重（8.94±0.51），增加CSA(1474±176.1 μm2)，减少胶原积累（胶原面积：3.04±0.74%，与IM相比均p < 0.05）。在体外，NaHS处理（30 μM）显著逆转h2o2诱导的肌管直径减小（19.16±0.91 μM比15.61±0.72 μM, p < 0.01）和融合指数提高（46.47±1.51%比35.28±2.87%,p < 0.05）。Western blot分析显示，NaHS上调了SESN2和Nrf2以及下游抗氧化蛋白HO-1和NQO1的表达（p < 0.05），而SESN2敲低则阻断了这些作用，并消除了NaHS介导的肌管保护作用。在SESN2-/-小鼠中，NaHS未能增加肌肉质量/体重（7.24±1.3比WT + NaHS 10.12±0.38,p < 0.001）， CSA（699.2±21.51 μm2比WT + NaHS 1189±93.27 μm2, p < 0.001）或抗氧化能力，证实了SESN2在介导h2s依赖性肌肉保护中的重要作用。结论sh2s通过SESN2/Nrf2信号通路增强抗氧化防御能力，对废用性肌肉萎缩具有保护作用。这些发现表明H2S是一种潜在的运动模拟治疗策略，可以保持肌肉质量和功能。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Cachexia Sarcopenia and Muscle MEDICINE, GENERAL & INTERNAL-

CiteScore

13.30

自引率

12.40%

发文量

234

审稿时长

16 weeks

期刊介绍： The Journal of Cachexia, Sarcopenia and Muscle is a peer-reviewed international journal dedicated to publishing materials related to cachexia and sarcopenia, as well as body composition and its physiological and pathophysiological changes across the lifespan and in response to various illnesses from all fields of life sciences. The journal aims to provide a reliable resource for professionals interested in related research or involved in the clinical care of affected patients, such as those suffering from AIDS, cancer, chronic heart failure, chronic lung disease, liver cirrhosis, chronic kidney failure, rheumatoid arthritis, or sepsis.