The developing cardiac myocyte: Maturation of excitability and excitation-contraction coupling

The study of cardiac myocyte (CM) differentiation, development, and maturation is of interest for several compelling reasons. First, mechanisms of development are of fundamental biological interest. Second, congenital malformation of the heart may be related to CM dysfunction during embryonic/fetal development. Third, adult myocardium in a variety of diseased states re-expresses a fetal-like gene program. Fourth, the mature heart cannot readily regenerate itself. Thus, cell replacement therapy is an emerging treatment paradigm. Among the obstacles for the realization of cell replacement therapy is our incomplete understanding of the function during CM maturation. This is crucial in the potential use of embryonic stem (ES) cell-derived CMs as a cell source. Although much progress has been realized with mouse ES-CMs, our understanding of human counterparts is scant. Here we discuss key molecular underpinnings of excitability and excitation-contraction coupling in developing mouse heart. We focus on the Ca channel multimeric complex and Ca handling. We compare mouse embryonic physiology to that previously described in mouse ES-CMs and draw parallels and highlight distinctions to human ES-CMs. During mouse embryonic and fetal maturation, the L-type Ca channel current (I_Ca,L) predominates, but embryonic/fetal I_Ca,L has distinct properties from mature I_Ca,L. In addition T-type Ca current (I_Ca,T) present in the fetus is not present in the adult. It is neither ethical nor practical to experiment with live human embryonic/fetal CMs for I_Ca and Ca handling studies, but we can draw inferences from human heart cell function based on studies of human ES-CMs, using the parallels noted between mouse embryonic heart cells and mouse ES-CMs.