de Carvalho Ana Elisa Teófilo Saturi, Bassaneze Vinícius, Forni Maria Fernanda, Keusseyan Aline Alfonso, Kowaltowski Alicia Juliana, Krieger José Eduardo
Laboratory of Genetics and Molecular Cardiology/LIM 13, Heart Institute (InCor- HCFMUSP), University of São Paulo Medical School, São Paulo, Brazil.
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
Sci Rep. 2017 Nov 13;7(1):15434. doi: 10.1038/s41598-017-15656-3.
Cardiac energy metabolism must cope with early postnatal changes in tissue oxygen tensions, hemodynamics, and cell proliferation to sustain development. Here, we tested the hypothesis that proliferating neonatal cardiomyocytes are dependent on high oxidative energy metabolism. We show that energy-related gene expression does not correlate with functional oxidative measurements in the developing heart. Gene expression analysis suggests a gradual overall upregulation of oxidative-related genes and pathways, whereas functional assessment in both cardiac tissue and cultured cardiomyocytes indicated that oxidative metabolism decreases between the first and seventh days after birth. Cardiomyocyte extracellular flux analysis indicated that the decrease in oxidative metabolism between the first and seventh days after birth was mostly related to lower rates of ATP-linked mitochondrial respiration, suggesting that overall energetic demands decrease during this period. In parallel, the proliferation rate was higher for early cardiomyocytes. Furthermore, in vitro nonlethal chemical inhibition of mitochondrial respiration reduced the proliferative capacity of early cardiomyocytes, indicating a high energy demand to sustain cardiomyocyte proliferation. Altogether, we provide evidence that early postnatal cardiomyocyte proliferative capacity correlates with high oxidative energy metabolism. The energy requirement decreases as the proliferation ceases in the following days, and both oxidative-dependent metabolism and anaerobic glycolysis subside.
心脏能量代谢必须应对出生后早期组织氧张力、血流动力学和细胞增殖的变化，以维持心脏发育。在此，我们验证了一个假说，即增殖的新生心肌细胞依赖于高氧化能量代谢。我们发现，在发育中的心脏中，与能量相关的基因表达与功能性氧化测量结果并不相关。基因表达分析表明，氧化相关基因和通路总体呈逐渐上调趋势，而对心脏组织和培养的心肌细胞进行的功能评估表明，出生后第1天到第7天，氧化代谢降低。心肌细胞胞外流量分析表明，出生后第1天到第7天氧化代谢的降低主要与ATP相关的线粒体呼吸速率降低有关，这表明在此期间总体能量需求减少。与此同时，早期心肌细胞的增殖率更高。此外，体外对线粒体呼吸进行非致死性化学抑制会降低早期心肌细胞的增殖能力，这表明维持心肌细胞增殖需要高能量需求。总之，我们提供的证据表明，出生后早期心肌细胞的增殖能力与高氧化能量代谢相关。随着随后几天增殖停止，能量需求降低，氧化依赖性代谢和无氧糖酵解均减弱。
