Department of Physiology, Michigan State University , East Lansing, Michigan.
Department of Radiology, Michigan State University , East Lansing, Michigan.
Am J Physiol Regul Integr Comp Physiol. 2019 Jan 1;316(1):R76-R86. doi: 10.1152/ajpregu.00321.2018. Epub 2018 Nov 21.
During aerobic exercise (>65% of maximum oxygen consumption), the primary source of acetyl-CoA to fuel oxidative ATP synthesis in muscle is the pyruvate dehydrogenase (PDH) reaction. This study investigated how regulation of PDH activity affects muscle energetics by determining whether activation of PDH with dichloroacetate (DCA) alters the dynamics of the phosphate potential of rat gastrocnemius muscle during contraction. Twitch contractions were induced in vivo over a broad range of intensities to sample submaximal and maximal aerobic workloads. Muscle phosphorus metabolites were measured in vivo before and after DCA treatment by phosphorus nuclear magnetic resonance spectroscopy. At rest, DCA increased PDH activation compared with control (90 ± 12% vs. 23 ± 3%, P < 0.05), with parallel decreases in inorganic phosphate (P) of 17% (1.4 ± 0.2 vs. 1.7 ± 0.1 mM, P < 0.05) and an increase in the free energy of ATP hydrolysis (ΔG) (-66.2 ± 0.3 vs. -65.6 ± 0.2 kJ/mol, P < 0.05). During stimulation DCA increased steady-state phosphocreatine (PCr) and the magnitude of ΔG, with concomitant reduction in P and ADP concentrations. These effects were not due to kinetic alterations in PCr hydrolysis, resynthesis, or glycolytic ATP production and altered the flow-force relationship between mitochondrial ATP synthesis rate and ΔG. DCA had no significant effect at 1.0- to 2.0-Hz stimulation because physiological mechanisms at these high stimulation levels cause maximal activation of PDH. These data support a role of PDH activation in the regulation of the energetic steady state by altering the phosphate potential (ΔG) at rest and during contraction.
在有氧运动（>最大耗氧量的 65%）中，肌肉中氧化型三磷酸腺苷合成的乙酰辅酶 A 的主要来源是丙酮酸脱氢酶（PDH）反应。本研究通过确定二氯乙酸（DCA）激活 PDH 是否会改变大鼠比目鱼肌收缩过程中磷酸势能的动力学，来研究 PDH 活性的调节如何影响肌肉能量学。通过在广泛的强度范围内在体内诱导抽搐收缩，以采样亚最大和最大有氧工作量。通过磷磁共振波谱在 DCA 处理前后在体内测量肌肉磷代谢物。在休息时，与对照相比，DCA 增加了 PDH 的激活（90±12%比 23±3%，P<0.05），无机磷（P）平行下降 17%（1.4±0.2 比 1.7±0.1 mM，P<0.05）和 ATP 水解的自由能（ΔG）增加（-66.2±0.3 比-65.6±0.2 kJ/mol，P<0.05）。在刺激过程中，DCA 增加了磷酸肌酸（PCr）的稳态和ΔG 的幅度，同时降低了 P 和 ADP 的浓度。这些效应不是由于 PCr 水解、再合成或糖酵解 ATP 产生的动力学改变引起的，改变了线粒体 ATP 合成速率和ΔG 之间的流量-力关系。在 1.0-2.0 Hz 的刺激下，DCA 没有显著影响，因为在这些高刺激水平下的生理机制导致 PDH 的最大激活。这些数据支持 PDH 激活在通过改变休息和收缩期间的磷酸势能（ΔG）来调节能量稳态中的作用。
