Enhanced N-terminal degradation of troponin I blunts cardiac function responsiveness to isoproterenol in 4-week tail-suspended rats

Abstract

The N-terminal extension of cardiac troponinI (cTnI) is important in regulating cardiac function. Although the normal rat myocardium shows some cTnI N-terminal degradation (cTnI-ND), exposure to 4weeks of tail-suspension markedly increased cTnI-ND. We hypothesized that the increased cTnI-ND in tail-suspended rats may affect cardiac function, particularly during β-adrenergic (β-A) stimulation. The increase in cardiac output with isoproterenol (ISO) treatment was smaller in tail-suspended rats compared with controls. Left ventricular end-diastolic pressure was elevated and increases in maximal rates of left ventricular pressure development and relaxation were lower during ISO treatment in tail-suspended rats. Response to ISO, forskolin, DB-cAMP and IBMX was also lower in cardiomyocytes from tail-suspended rats. The increase in shortening and re-lengthening the rates of cardiomyocytes at a maximal dose of ISO, forskolin, DB-cAMP and IBMX treatment was limited in tail-suspended rats. There was no difference in Ca2+ sensitivity of the isometric force between tail-suspended and control rats, although Ca2+ sensitivity was decreased less in tail-suspended rats versus control rats during PKA phosphorylation. There was no difference in PKA protein expression and activation during ISO stimulation between the twogroups. Due to the increase in cTnI-ND, ISO-induced phosphorylation of cTnI was reduced in tail-suspended rats. The total phospholamban expression and phosphorylation by ISO was unaltered in tail-suspended rat hearts. These data suggest that enhanced cTnI-ND following 4-week tail-suspension is a major component of the β-A receptor signaling pathway, depressing cardiac function under ISO stimulation.