For patients with heart failure, myocardial ATP level can be reduced to one-half of that observed in healthy controls. This marked reduction (from ≈8 mM in healthy controls to as low as 3–4 mM in heart failure) has been suggested to contribute to impaired myocardial contraction and to the decreased pump function characteristic of heart failure. However, in vitro measures of maximum myofilament force generation, maximum shortening velocity, and the actomyosin ATPase activity show effective K_M values for MgATP ranging from ≈10 μM to 150 μM, well below the intracellular ATP level in heart failure. Thus, it is not clear that the fall of myocardial ATP observed in heart failure is sufficient to impair the function of the contractile proteins. Therefore, we tested the effect of low MgATP levels on myocardial contraction using demembranated cardiac muscle preparations that were exposed to MgATP levels typical of the range found in non-failing and failing hearts. Consistent with previous studies, we found that a 50% reduction in MgATP level (from 8 mM to 4 mM) did not reduce maximum force generation or maximum velocity of shortening. However, we found that a 50% reduction in MgATP level caused a 20%–25% reduction in maximal power generation (measured during muscle shortening against a load) and a 20% slowing of cross-bridge cycling kinetics. These results suggest that the decreased cellular ATP level occurring in heart failure contributes to the impaired pump function of the failing heart. Since the ATP-myosin ATPase dissociation constant is estimated to be submillimolar, these findings also suggest that MgATP concentration affects cross-bridge dynamics through a mechanism that is more complex than through the direct dependence of MgATP concentration on myosin ATPase activity. Finally, these studies suggest that therapies targeted to increase adenine nucleotide pool levels in cardiomyocytes might be beneficial for treating heart failure.

对于心力衰竭患者，心肌 ATP 水平可降至健康对照者的一半。这种显着的降低（从健康对照组的约 8 mM 到心力衰竭的低至 3-4 mM）被认为会导致心肌收缩受损和心力衰竭特征的泵功能下降。然而，最大肌丝力产生、最大缩短速度和肌动球蛋白 ATP 酶活性的体外测量显示 MgATP 的有效K _M值范围为 约 10 μM 至 150 μM，远低于心力衰竭时的细胞内 ATP 水平。因此，尚不清楚在心力衰竭中观察到的心肌 ATP 下降是否足以损害收缩蛋白的功能。因此，我们使用脱膜心肌制剂测试了低 MgATP 水平对心肌收缩的影响，该制剂暴露于非衰竭心脏和衰竭心脏中典型的 MgATP 水平范围。与之前的研究一致，我们发现 MgATP 水平降低 50%（从 8 mM 至 4 mM）并不会降低最大力产生或最大缩短速度。然而，我们发现 MgATP 水平降低 50% 会导致最大发电量降低 20%–25%（在肌肉对抗负载时缩短时测量），并且过桥循环动力学减慢 20%。这些结果表明，心力衰竭时细胞 ATP 水平降低会导致心力衰竭的泵功能受损。由于 ATP-肌球蛋白 ATP 酶解离常数估计为亚毫摩尔，这些发现还表明 MgATP 浓度通过一种比 MgATP 浓度对肌球蛋白 ATP 酶活性的直接依赖性更复杂的机制影响跨桥动力学。最后，这些研究表明，旨在增加心肌细胞中腺嘌呤核苷酸库水平的疗法可能有益于治疗心力衰竭。