Altered Ca(2+) signaling in skeletal muscle fibers of the R6/2 mouse, a model of Huntington's disease.
J Gen Physiol
; 144(5): 393-413, 2014 Nov.
Article
em En
| MEDLINE
| ID: mdl-25348412
ABSTRACT
Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat within the gene encoding the protein huntingtin. The resulting elongated glutamine (poly-Q) sequence of mutant huntingtin (mhtt) affects both central neurons and skeletal muscle. Recent reports suggest that ryanodine receptor-based Ca(2+) signaling, which is crucial for skeletal muscle excitation-contraction coupling (ECC), is changed by mhtt in HD neurons. Consequently, we searched for alterations of ECC in muscle fibers of the R6/2 mouse, a mouse model of HD. We performed fluorometric recordings of action potentials (APs) and cellular Ca(2+) transients on intact isolated toe muscle fibers (musculi interossei), and measured L-type Ca(2+) inward currents on internally dialyzed fibers under voltage-clamp conditions. Both APs and AP-triggered Ca(2+) transients showed slower kinetics in R6/2 fibers than in fibers from wild-type mice. Ca(2+) removal from the myoplasm and Ca(2+) release flux from the sarcoplasmic reticulum were characterized using a Ca(2+) binding and transport model, which indicated a significant reduction in slow Ca(2+) removal activity and Ca(2+) release flux both after APs and under voltage-clamp conditions. In addition, the voltage-clamp experiments showed a highly significant decrease in L-type Ca(2+) channel conductance. These results indicate profound changes of Ca(2+) turnover in skeletal muscle of R6/2 mice and suggest that these changes may be associated with muscle pathology in HD.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Huntington
/
Fibras Musculares Esqueléticas
/
Sinalização do Cálcio
Limite:
Animals
Idioma:
En
Revista:
J Gen Physiol
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Alemanha