San-Millan Iñigo, Sparagna Genevieve C, Chapman Hailey L, Warkins Valerie L, Chatfield Kathryn C, Shuff Sydney R, Martinez Janel L, Brooks George A
Department of Human Physiology and Nutrition, University of Colorado, Colorado Springs, CO, United States.
Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
Front Nutr. 2022 Mar 4;9:809485. doi: 10.3389/fnut.2022.809485. eCollection 2022.
Lactate is an important signaling molecule with autocrine, paracrine and endocrine properties involved in multiple biological processes including regulation of gene expression and metabolism. Levels of lactate are increased chronically in diseases associated with cardiometabolic disease such as heart failure, type 2 diabetes, and cancer. Using neonatal ventricular myocytes, we tested the hypothesis that chronic lactate exposure could decrease the activity of cardiac mitochondria that could lead to metabolic inflexibility in the heart and other tissues.
Neonatal rat ventricular myocytes (NRVMs) were treated for 48 h with 5, 10, or 20 mM lactate and CPT I and II activities were tested using radiolabelled assays. The molecular species profile of the major mitochondrial phospholipid, cardiolipin, was determined using electrospray ionization mass spectrometry along with reactive oxygen species (ROS) levels measured by Amplex Red and mitochondrial oxygen consumption using the Seahorse analyzer.
CPT I activity trended downward ( = 0.07) and CPT II activity significantly decreased with lactate exposure ( < 0.001). Cardiolipin molecular species containing four 18 carbon chains (72 carbons total) increased with lactate exposure, but species of other sizes decreased significantly. Furthermore, ROS production was strongly enhanced with lactate ( < 0.001) and mitochondrial ATP production and maximal respiration were both significantly down regulated with lactate exposure ( < 0.05 and < 0.01 respectively).
Chronic lactate exposure in cardiomyocytes leads to a decrease in fatty acid transport, alterations of cardiolipin remodeling, increases in ROS production and decreases in mitochondrial oxygen consumption that could have implications for both metabolic health and flexibility. The possibility that both intra-, or extracellular lactate levels play roles in cardiometabolic disease, heart failure, and other forms of metabolic inflexibility needs to be assessed .
乳酸是一种重要的信号分子，具有自分泌、旁分泌和内分泌特性，参与包括基因表达调控和代谢在内的多种生物学过程。在与心脏代谢疾病相关的疾病如心力衰竭、2型糖尿病和癌症中，乳酸水平会长期升高。我们使用新生大鼠心室肌细胞，检验了慢性乳酸暴露会降低心脏线粒体活性，进而导致心脏和其他组织代谢灵活性降低这一假说。
将新生大鼠心室肌细胞（NRVMs）用5、10或20 mM乳酸处理48小时，并用放射性标记测定法检测肉碱棕榈酰转移酶I（CPT I）和II的活性。使用电喷雾电离质谱法测定主要线粒体磷脂心磷脂的分子种类谱，同时用Amplex Red测量活性氧（ROS）水平，并用海马分析仪测量线粒体氧消耗。
随着乳酸暴露，CPT I活性呈下降趋势（P = 0.07），CPT II活性显著降低（P < 0.001）。含有四条18碳链（共72个碳）的心磷脂分子种类随着乳酸暴露而增加，但其他大小的种类显著减少。此外，乳酸强烈增强了ROS的产生（P < 0.001），并且随着乳酸暴露，线粒体ATP产生和最大呼吸均显著下调（分别为P < 0.05和P < 0.01）。
心肌细胞中的慢性乳酸暴露导致脂肪酸转运减少、心磷脂重塑改变、ROS产生增加以及线粒体氧消耗减少，这可能对代谢健康和灵活性产生影响。需要评估细胞内或细胞外乳酸水平在心脏代谢疾病、心力衰竭和其他形式的代谢灵活性降低中是否起作用。
