CSE/H 2 S/SESN2 Signalling Mediates the Protective Effect of Exercise Against Immobilization‐Induced Muscle Atrophy in Mice

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ABSTRACT Background Hydrogen sulphide (H 2 S), 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 H 2 S donor NaHS (30 μmol/kg) or the CSE inhibitor DL‐propargylglycine (PAG, 50 mg/kg). In vitro, C 2 C 12 myotubes were treated with H 2 O 2 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 μm 2 vs. 905.5 ± 88.52 μm 2 , 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 μm 2 , collagen area: 5.04 ± 0.66%, all p < 0.05 vs. IM + EX). Conversely, administration of the H 2 S donor NaHS mimicked the protective effects of exercise, increasing muscle mass/body weight (8.94 ± 0.51), CSA (1474 ± 176.1 μm 2 ) and reducing collagen accumulation (collagen area: 3.04 ± 0.74%, all p < 0.05 vs. IM). In vitro, NaHS treatment (30 μM) significantly reversed H 2 O 2 ‐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 μm 2 vs. WT + NaHS 1189 ± 93.27 μm 2 , p < 0.001) or antioxidant capacity, confirming the essential role of SESN2 in mediating H 2 S‐dependent muscle protection. Conclusions H 2 S protects against disuse‐induced muscle atrophy by enhancing antioxidant defences via the SESN2/Nrf2 signalling pathway. These findings identify H 2 S as a potential exercise‐mimetic therapeutic strategy for preserving muscle mass and function.

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