The effects of slow skeletal troponin I expression in the murine myocardium are influenced by development‐related shifts in myosin heavy chain isoform
Authors: Ford Steven J. , Chandra Murali 
Published: September 2012

Key points

Slow skeletal troponin I (ssTnI) transgenic (TG) mice were treated with propylthiouracil (PTU) to induce a shift in myosin heavy chain (MHC) from the α‐ to β‐MHC isoform, to understand how concomitant expression of these proteins affects cardiac muscle function.

Following PTU treatment, β‐MHC expression increased to ∼80%, relative to α‐MHC while TG ssTnI expression persisted at a level of ∼34% of total TnI.

ssTnI sped XB recruitment dynamics, and this increase was enhanced ∼3.8‐fold in the presence of β‐MHC when compared to ssTnI effects against α‐MHC.

The ssTnI effect to increase myofilament Ca2+ sensitivity was blunted in the presence of β‐MHC.

Our results provide new evidence for significant TnI–MHC interactions in their effects on cardiac function, which has major implications for coupling between concerted expression of contractile regulatory isoforms and the thick and thin filament‐mediated tuning of cardiac contractile function.

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 (β‐MHC) isoforms. Cardiac muscle fibres from these mice contained ∼80%β‐MHC and ∼34% ssTnI of total MHC or TnI, respectively, allowing us to test the functional effects of ssTnI in the presence of β‐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, Ca2+‐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 β‐MHC was present. Another major finding was that the previously documented ssTnI‐mediated increase in myofilament Ca2+ sensitivity (pCa50) was blunted when β‐MHC was present. ssTnI expression increased pCa50 by 0.33 in α‐MHC fibres, whereas ssTnI increased pCa50 by only 0.05 in β‐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 Ca2+‐handling mechanisms are underdeveloped, and to prevent excessive ssTnI‐dependent inotropy (increased Ca2+ sensitivity) in the embryonic myocardium.