Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure.
Nat Commun
; 10(1): 5754, 2019 12 17.
Article
em En
| MEDLINE
| ID: mdl-31848331
ABSTRACT
Heart failure is the major cause of death for muscular dystrophy patients, however, the molecular pathomechanism remains unknown. Here, we show the detailed molecular pathogenesis of muscular dystrophy-associated cardiomyopathy in mice lacking the fukutin gene (Fktn), the causative gene for Fukuyama muscular dystrophy. Although cardiac Fktn elimination markedly reduced α-dystroglycan glycosylation and dystrophin-glycoprotein complex proteins in sarcolemma at all developmental stages, cardiac dysfunction was observed only in later adulthood, suggesting that membrane fragility is not the sole etiology of cardiac dysfunction. During young adulthood, Fktn-deficient mice were vulnerable to pathological hypertrophic stress with downregulation of Akt and the MEF2-histone deacetylase axis. Acute Fktn elimination caused severe cardiac dysfunction and accelerated mortality with myocyte contractile dysfunction and disordered Golgi-microtubule networks, which were ameliorated with colchicine treatment. These data reveal fukutin is crucial for maintaining myocyte physiology to prevent heart failure, and thus, the results may lead to strategies for therapeutic intervention.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Problema de saúde:
6_cardiovascular_diseases
/
6_musculoskeletal_diseases_rheumatic_disorders
/
6_other_circulatory_diseases
Assunto principal:
Transferases
/
Músculo Esquelético
/
Miócitos Cardíacos
/
Insuficiência Cardíaca
/
Distrofias Musculares
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Adult
/
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Nat Commun
Assunto da revista:
BIOLOGIA
/
CIENCIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Japão