Physiological role for S-nitrosylation of RyR1 in skeletal muscle function and development.
Biochem Biophys Res Commun
; 723: 150163, 2024 Sep 03.
Article
en En
| MEDLINE
| ID: mdl-38820626
ABSTRACT
Excitation-contraction coupling in skeletal muscle myofibers depends upon Ca2+ release from the sarcoplasmic reticulum through the ryanodine receptor/Ca2+-release channel RyR1. The RyR1 contains â¼100 Cys thiols of which â¼30 comprise an allosteric network subject to posttranslational modification by S-nitrosylation, S-palmitoylation and S-oxidation. However, the role and function of these modifications is not understood. Although aberrant S-nitrosylation of multiple unidentified sites has been associated with dystrophic diseases, malignant hyperthermia and other myopathic syndromes, S-nitrosylation in physiological situations is reportedly specific to a single (1 of â¼100) Cys in RyR1, Cys3636 in a manner gated by pO2. Using mice expressing a form of RyR1 with a Cys3636âAla point mutation to prevent S-nitrosylation at this site, we showed that Cys3636 was the principal target of endogenous S-nitrosylation during normal muscle function. The absence of Cys3636 S-nitrosylation suppressed stimulus-evoked Ca2+ release at physiological pO2 (at least in part by altering the regulation of RyR1 by Ca2+/calmodulin), eliminated pO2 coupling, and diminished skeletal myocyte contractility in vitro and measures of muscle strength in vivo. Furthermore, we found that abrogation of Cys3636 S-nitrosylation resulted in a developmental defect reflected in diminished myofiber diameter, altered fiber subtypes, and altered expression of genes implicated in muscle development and atrophy. Thus, our findings establish a physiological role for pO2-coupled S-nitrosylation of RyR1 in skeletal muscle contractility and development and provide foundation for future studies of RyR1 modifications in physiology and disease.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Músculo Esquelético
/
Canal Liberador de Calcio Receptor de Rianodina
Límite:
Animals
Idioma:
En
Revista:
Biochem Biophys Res Commun
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos