Phosphodiesterases S-sulfhydration contributes to human skeletal muscle function.
Pharmacol Res
; 177: 106108, 2022 03.
Article
en En
| MEDLINE
| ID: mdl-35121122
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 (H2S) 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 H2S 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.
Palabras clave
3-Isobutyl-1-methylxanthine (PubChem CID: 3758); 3-dione (DAz-2; 4-(3-Azidopropyl)cyclohexane-1; 4-Chloro-7-nitrobenzofurazan (NBF-Cl; Cyanine5 alkyne (PubChem CID: 131632191); Human Malignant Hyperthermia; Phosphodiesterases; PubChem CID: 25043); PubChem CID: 53394137); Rolipram (PubChem CID: 5092); S-sulfhydration; Sildenafil citrate (PubChem CID: 135413523); Skeletal muscle; Sodium hydrogen sulfide (PubChem CID: 28015)
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Hidrolasas Diéster Fosfóricas
/
Hipertermia Maligna
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Pharmacol Res
Asunto de la revista:
FARMACOLOGIA
Año:
2022
Tipo del documento:
Article
País de afiliación:
Italia