Smimmo M, Casale V, D'Andrea D, Bello I, Iaccarino N, Romano F, Brancaleone V, Panza E, d'Emmanuele di Villa Bianca R, Katsouda A, Mitidieri E, Antoniadou I, Papapetropoulos A, Maione F, Castaldo S, Friuli M, Romano A, Gaetani S, Sorrentino R, Randazzo A, Cirino G, Bucci M, Filipovic M, Vellecco V
Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.
School of Molecular Biosciences, University of Glasgow, UK; Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V. Dortmund, Germany.
Redox Biol. 2025 Jun;83:103645. doi: 10.1016/j.redox.2025.103645. Epub 2025 Apr 22.
Ectopic fat deposition in skeletal muscle (SKM) due to obesity leads to biochemical and morphological alterations that deteriorate SKM quality and performance. Here, we show that impaired MPST-derived hydrogen sulfide (HS) signaling contributes to obesity-related SKM dysfunction. Muscle tissues from obese db/db mice exhibit reduced MPST expression, correlating with decreased protein persulfidation and muscle performance in vivo. Mpst mice show similar deficits as db/db mice, confirming the role of MPST. HS supplementation improves locomotor activity in db/db mice and restores protein persulfidation, including SIRT-1. Myotubes placed in an "obese environment" display a downregulation of MPST, coupled with a reduced SIRT-1 persulfidation leading to an inflammatory state. Exogenous HS exerts beneficial effects recovering SIRT-1 persulfidation/activity. Finally, muscle biopsies from obese individuals show reduced MPST expression, underscoring the translational relevance to human SKM health. Our study unveils a crucial role for MPST-derived HS in obesity-associated SKM dysfunction via SIRT-1 persulfidation, highlighting the importance of the MPST/HS pathway in maintaining healthy SKM function.
肥胖导致的骨骼肌（SKM）异位脂肪沉积会引起生化和形态学改变，从而使SKM质量和性能下降。在此，我们表明，MPST衍生的硫化氢（HS）信号受损会导致与肥胖相关的SKM功能障碍。肥胖的db/db小鼠的肌肉组织中MPST表达降低，这与体内蛋白质过硫化作用的降低和肌肉性能相关。Mpst基因敲除小鼠表现出与db/db小鼠类似的缺陷，证实了MPST的作用。补充HS可改善db/db小鼠的运动活性，并恢复包括SIRT-1在内的蛋白质过硫化作用。置于“肥胖环境”中的肌管显示MPST下调，同时SIRT-1过硫化作用降低，导致炎症状态。外源性HS发挥有益作用，恢复SIRT-1的过硫化作用/活性。最后，肥胖个体的肌肉活检显示MPST表达降低，强调了该研究与人类SKM健康的转化相关性。我们的研究揭示了MPST衍生的HS通过SIRT-1过硫化作用在肥胖相关的SKM功能障碍中起关键作用，突出了MPST/HS途径在维持健康SKM功能中的重要性。
