Gao W D, Pérez N G, Seidman C E, Seidman J G, Marbán E
Section of Molecular and Cellular Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
J Clin Invest. 1999 Mar;103(5):661-6. doi: 10.1172/JCI5220.
Excitation-contraction coupling in cardiac muscle of familial hypertrophic cardiomyopathy (FHC) remains poorly understood, despite the fact that the genetic alterations are well defined. We characterized calcium cycling and contractile activation in trabeculae from a mutant mouse model of FHC (Arg403Gln knockin, alpha-myosin heavy chain). Wild-type mice of the same strain and age ( approximately 20 weeks old) served as controls. During twitch contractions, peak intracellular Ca2+ ([Ca2+]i) was higher in mutant muscles than in the wild-type (P < 0.05), but force development was equivalent in the two groups. Ca2+ transient amplitude increased dramatically in both groups as stimulation rate increased from 0.2 to 4 Hz. Nevertheless, developed force fell at the higher stimulation rates in the mutants but not in controls (P < 0.05). The steady-state force-[Ca2+]i relationship was less steep in mutants (Hill coefficient, 2.94 +/- 0.27 vs. 5.28 +/- 0.64; P > 0.003), with no changes in the [Ca2+]i required for 50% activation or maximal Ca2+-activated force. Thus, calcium cycling and myofilament properties are both altered in FHC mutant mice: more Ca2+ is mobilized to generate force, but this does not suffice to maintain contractility at high stimulation rates.
尽管家族性肥厚型心肌病（FHC）的基因改变已明确，但对其心肌中的兴奋-收缩偶联仍知之甚少。我们对FHC突变小鼠模型（Arg403Gln基因敲入，α-肌球蛋白重链）小梁中的钙循环和收缩激活进行了表征。相同品系和年龄（约20周龄）的野生型小鼠作为对照。在单收缩过程中，突变肌肉中的细胞内Ca2+峰值（[Ca2+]i）高于野生型（P < 0.05），但两组的力发展相当。随着刺激频率从0.2 Hz增加到4 Hz，两组的Ca2+瞬变幅度均显著增加。然而，在较高刺激频率下，突变体中的发展力下降，而对照组则没有（P < 0.05）。突变体中稳态力-[Ca2+]i关系较平缓（希尔系数，2.94±0.27对5.28±0.64；P > 0.003），50%激活所需的[Ca2+]i或最大Ca2+激活力无变化。因此，FHC突变小鼠的钙循环和肌丝特性均发生改变：动员更多的Ca2+来产生力，但这不足以在高刺激频率下维持收缩性。
