A Small-Molecule Approach to Restore a Slow-Oxidative Phenotype and Defective CaMKIIß Signaling in Limb Girdle Muscular Dystrophy.
Cell Rep Med
; 1(7): 100122, 2020 10 20.
Article
em En
| MEDLINE
| ID: mdl-33205074
ABSTRACT
Mutations in CAPN3 cause limb girdle muscular dystrophy R1 (LGMDR1, formerly LGMD2A) and lead to progressive and debilitating muscle wasting. Calpain 3 deficiency is associated with impaired CaMKIIß signaling and blunted transcriptional programs that encode the slow-oxidative muscle phenotype. We conducted a high-throughput screen on a target of CaMKII (Myl2) to identify compounds to override this signaling defect; 4 were tested in vivo in the Capn3 knockout (C3KO) model of LGMDR1. The leading compound, AMBMP, showed good exposure and was able to reverse the LGMDR1 phenotype in vivo, including improved oxidative properties, increased slow fiber size, and enhanced exercise performance. AMBMP also activated CaMKIIß signaling, but it did not alter other pathways known to be associated with muscle growth. Thus, AMBMP treatment activates CaMKII and metabolically reprograms skeletal muscle toward a slow muscle phenotype. These proof-of-concept studies lend support for an approach to the development of therapeutics for LGMDR1.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Calpaína
/
Cadeias Leves de Miosina
/
Miosinas Cardíacas
/
Distrofia Muscular do Cíngulo dos Membros
/
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina
/
Bibliotecas de Moléculas Pequenas
/
Proteínas Musculares
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article