Nox4 - RyR1 - Nox2: Regulators of micro-domain signaling in skeletal muscle.
Redox Biol
; 36: 101557, 2020 09.
Article
em En
| MEDLINE
| ID: mdl-32506037
ABSTRACT
The ability for skeletal muscle to perform optimally can be affected by the regulation of Ca2+ within the triadic junctional space at rest. Reactive oxygen species impact muscle performance due to changes in oxidative stress, damage and redox regulation of signaling cascades. The interplay between ROS and Ca2+ signaling at the triad of skeletal muscle is therefore important to understand as it can impact the performance of healthy and diseased muscle. Here, we aimed to examine how changes in Ca2+ and redox signaling within the junctional space micro-domain of the mouse skeletal muscle fibre alters the homeostasis of these complexes. The dystrophic mdx mouse model displays increased RyR1 Ca2+ leak and increased NAD(P)H Oxidase 2 ROS. These alterations make the mdx mouse an ideal model for understanding how ROS and Ca2+ handling impact each other. We hypothesised that elevated t-tubular Nox2 ROS increases RyR1 Ca2+ leak contributing to an increase in cytoplasmic Ca2+, which could then initiate protein degradation and impaired cellular functions such as autophagy and ER stress. We found that inhibiting Nox2 ROS did not decrease RyR1 Ca2+ leak observed in dystrophin-deficient skeletal muscle. Intriguingly, another NAD(P)H isoform, Nox4, is upregulated in mice unable to produce Nox2 ROS and when inhibited reduced RyR1 Ca2+ leak. Our findings support a model in which Nox4 ROS induces RyR1 Ca2+ leak and the increased junctional space [Ca2+] exacerbates Nox2 ROS; with the cumulative effect of disruption of downstream cellular processes that would ultimately contribute to reduced muscle or cellular performance.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Canal de Liberação de Cálcio do Receptor de Rianodina
/
Distrofia Muscular de Duchenne
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Redox Biol
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos