Reducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice.
Nat Commun
; 8(1): 1068, 2017 10 20.
Article
em En
| MEDLINE
| ID: mdl-29051551
ABSTRACT
Sarcolipin (SLN) is an inhibitor of the sarco/endoplasmic reticulum (SR) Ca2+ ATPase (SERCA) and is abnormally elevated in the muscle of Duchenne muscular dystrophy (DMD) patients and animal models. Here we show that reducing SLN levels ameliorates dystrophic pathology in the severe dystrophin/utrophin double mutant (mdxutr -/-) mouse model of DMD. Germline inactivation of one allele of the SLN gene normalizes SLN expression, restores SERCA function, mitigates skeletal muscle and cardiac pathology, improves muscle regeneration, and extends the lifespan. To translate our findings into a therapeutic strategy, we knock down SLN expression in 1-month old mdxutr -/- mice via adeno-associated virus (AAV) 9-mediated RNA interference. The AAV treatment markedly reduces SLN expression, attenuates muscle pathology and improves diaphragm, skeletal muscle and cardiac function. Taken together, our findings suggest that SLN reduction is a promising therapeutic approach for DMD.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteolipídeos
/
Terapia Genética
/
Regulação da Expressão Gênica
/
Distrofia Muscular de Duchenne
/
Inativação Gênica
/
Proteínas Musculares
/
Cardiomiopatias
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article