Troponin T isoform expression in humans. A comparison among normal and failing adult heart, fetal heart, and adult and fetal skeletal muscle.

Abstract

The expression of troponin (Tn) T, a thin-filament regulatory protein, was examined in left ventricular myocardium from normal and from failing adult human hearts. The differences in isoform expression between normal and failing myocardium led us to examine the ontogenic expression of TnT in human striated muscle. Left ventricular samples were obtained from patients with severe heart failure undergoing cardiac transplantation and normal adult organ donors. Fetal muscle was obtained from aborted fetuses after 14-15 weeks of gestation, and adult skeletal muscle was obtained from surgical biopsies. Western blots of normal and failing adult heart proteins demonstrated that two isoforms, TnT1 and TnT2, are expressed in different amounts, with TnT2 being significantly greater in failing hearts (p less than 0.004). Western blots of two-dimensional gels of these proteins resolved two predominant spots of both TnT1 and TnT2 and several minor TnT species. Alkaline phosphatase treatment converted the two major spots of each isoform into the single more basic spots. A comparison of the ATPase activities and the TnT2 percentage of total TnT in individual failing and normal adult hearts demonstrated an inverse and negative relation (r = 0.7, p less than 0.02). In the fetal heart, four TnT isoforms were found, two of which had the same electrophoretic mobilities as the adult cardiac isoforms TnT1 and TnT2. Fetal skeletal muscle expressed two of the four fetal cardiac TnT isoforms, one of which comigrated with adult cardiac TnT1. These cardiac isoforms were expressed in low abundance in fetal skeletal muscle relative to seven fast skeletal muscle TnT isoforms. No cardiac isoforms were present in adult skeletal muscle. Because many etiologies caused heart failure in the transplant patients, we propose that the disease-associated increased expression of the TnT isoform TnT2 is an adaptation to the heart failure state and a partial recapitulation of the fetal expression of cardiac TnT isoforms.

Altered Myocardial Thin-Filament Function in the Failing Dahl Salt-Sensitive Rat Heart

“…4 These data strongly suggest that thin-filament compositional changes in the Dahl rat contribute causally to the altered cross-bridge cycling that occurs during the transition to failure in this model. 6,9 This correlation is further supported Values are expressed as mean of fit to the Hill equationϮSEM. V max indicates maximal calcium-activated thin-filament velocity; pCa50, negative log of the calcium concentration at which NTF velocity is half maximal.…”

Myofibrillar remodelling in cardiac hypertrophy, heart failure and cardiomyopathies

“…Although TnT itself does not bind Ca 2+ , its allosteric effect on the troponin I (TnI)/troponin C (TnC) complex influences Ca 2+ sensitivity for tension development, depending on the concentration of Ca 2+ (82). The human heart expresses four TnT isoforms (cTnT 1 , cTnT 2 , cTnT 3 and cTnT 4 ) at the mRNA and protein levels; these are generated by an alternative splicing mechanism of the TnT gene (83)(84)(85). Isoform appearance is developmentally regulated: cTnT 3 predominates, while cTnT 4 is a minor (fetal) isoform in the adult human heart; the additional two fetal isoforms, cTnT 1 and cTnT 2 , are also present, but are barely detectable (86,87).…”

A Prospective Study of an Algorithm Using Cardiac Troponin I and Myoglobin as Adjuncts in the Diagnosis of Acute Myocardial Infarction and Intermediate Coronary Syndromes in a Veteran's Hospital

“…[19][20][21][22][23][24][25][26][27][28][29] Cardiac troponin I also remains elevated longer, usually up to 10-14 days.20 Recently it has also been shown that cTnI is an important prognostic indicator in patients presenting with unstable angina, even when CK-MB is not e l e~a t e d . l~\~&~~ Our study supports that notion.…”