Phosphodiesterases S-sulfhydration contributes to human skeletal muscle function. (March 2022)

• Record Type: Journal Article
• Authors: Vellecco, Valentina; Panza, Elisabetta; Bibli, Sofia-Iris; Casillo, Gian Marco; Raucci, Federica; Manzo, Onorina Laura; Smimmo, Martina; Villani, Romolo; Cavezza, Maria Rosaria; Fleming, Ingrid; d'Emmanuele di Villa Bianca, Roberta; Maione, Francesco; Cirino, Giuseppe; Bucci, Mariarosaria
• Is Part Of: Pharmacological research. Volume 177(2022)
• Publication Date: 2022-03
• Subjects: 3-Isobutyl-1-methylxanthine (PubChem CID: 3758) -- Sildenafil citrate (PubChem CID: 135413523) -- Rolipram (PubChem CID: 5092) -- Sodium hydrogen sulfide (PubChem CID: 28015) -- 4-(3-Azidopropyl)cyclohexane-1 -- 3-dione (DAz-2 -- PubChem CID: 53394137) -- Cyanine5 alkyne (PubChem CID: 131632191) -- 4-Chloro-7-nitrobenzofurazan (NBF-Cl -- PubChem CID: 25043); PDE phosphodiesterases -- MH malignant hyperthermia -- MHN malignant hyperthermia negative -- MHS malignant hyperthermia susceptible -- IVCT In Vitro Contracture Test -- SKM skeletal muscle -- PTM post-translational modification; S-sulfhydration -- Phosphodiesterases -- Human Malignant Hyperthermia -- Skeletal muscle; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106108
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: The increase in intracellular calcium is influenced by cyclic nucleotides (cAMP and cGMP) content, which rating is governed by phosphodiesterases (PDEs) activity.Despite it has been demonstrated a beneficial effect of PDEs inhibitors in different pathological conditions involving SKM, not much is known on the role exerted by cAMP-cGMP/PDEs axis in human SKM contractility. Here, we show that Ssulfhydration of PDEs modulates human SKM contractility in physiological and pathological conditions. Having previously demonstrated that, in the rare human syndrome Malignant Hyperthermia (MH), there is an overproduction of hydrogen sulfide (H2 S) within SKM contributing to hyper-contractility, here we have used MH negative diagnosed biopsies (MHN) as healthy SKM, and MH susceptible diagnosed biopsies (MHS) as a pathological model of SKM hypercontractility. The study has been performed on MHS and MHN human biopsies after diagnosis has been made and on primary SKM cells derived from both MHN and MHS biopsies. Our data demonstrate that in normal conditions PDEs are S-sulfhydrated in both quadriceps' biopsies and primary SKM cells. This post translational modification (PTM) negatively regulates PDEs activity with consequent increase of both cAMP and cGMP levels. In hypercontractile biopsies, due to an excessive H2 S content, there is an enhanced Ssulfhydration of PDEs that further increases cyclic nucleotides levels contributing to SKM hyper-contractility. Thus, the identification of a new endogenous PTM modulating PDEs activity represents an advancement in SKM physiopathology understanding. Graphical Abstract: ga1 Highlights: In human SKM, H2 S negatively regulates PDEs activity by S-sulfhydration. PDEs S-sulfhydration increases cyclic nucleotides levels enhancing SKM contractility. High levels of H2 S accounts for the SKM hyper-contractility observed in MH patients.