The effects of slow skeletal troponin I expression in the murine myocardium are influenced by development-related shifts in myosin heavy chain isoform.
J Physiol
; 590(23): 6047-63, 2012 Dec 01.
Article
em En
| MEDLINE
| ID: mdl-22966157
ABSTRACT
Troponin I (TnI) and myosin heavy chain (MHC) are two contractile regulatory proteins that undergo major shifts in isoform expression as cardiac myocytes mature from embryonic to adult stages. To date, many studies have investigated individual effects of embryonic vs. cardiac isoforms of either TnI or MHC on cardiac muscle function and contractile dynamics. Thus, we sought to determine whether concomitant expression of the embryonic isoforms of both TnI and MHC had functional effects that were not previously observed. Adult transgenic (TG) mice that express the embryonic isoform of TnI, slow skeletal TnI (ssTnI), were treated with propylthiouracil (PTU) to revert MHC expression from adult (α-MHC) to embryonic (ß-MHC) isoforms. Cardiac muscle fibres from these mice contained â¼80% ß-MHC and â¼34% ssTnI of total MHC or TnI, respectively, allowing us to test the functional effects of ssTnI in the presence of ß-MHC. Detergent-skinned cardiac muscle fibre bundles were used to study how the interplay between MHC and TnI modulate muscle length-mediated effect on crossbridge (XB) recruitment dynamics, Ca(2+)-activated tension, and ATPase activity. One major finding was that the model-predicted XB recruitment rate (b) was enhanced significantly by ssTnI, and this speeding effect of ssTnI on XB recruitment rate was much greater (3.8-fold) when ß-MHC was present. Another major finding was that the previously documented ssTnI-mediated increase in myofilament Ca(2+) sensitivity (pCa(50)) was blunted when ß-MHC was present. ssTnI expression increased pCa(50) by 0.33 in α-MHC fibres, whereas ssTnI increased pCa(50) by only 0.05 in ß-MHC fibres. Our study provides new evidence for significant interplay between MHC and TnI isoforms that is essential for tuning cardiac contractile function. Thus, MHC-TnI interplay may provide a developmentally dependent mechanism to enhance XB recruitment dynamics at a time when Ca(2+)-handling mechanisms are underdeveloped, and to prevent excessive ssTnI-dependent inotropy (increased Ca(2+) sensitivity) in the embryonic myocardium.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cadeias Pesadas de Miosina
/
Troponina I
/
Coração
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article