Sánchez-Aguilera Pablo, López-Crisosto Camila, Norambuena-Soto Ignacio, Penannen Christian, Zhu Jumo, Bomer Nils, Hoes Matijn F, Van Der Meer Peter, Chiong Mario, Westenbrink B Daan, Lavandero Sergio
Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
Front Physiol. 2023 Feb 8;14:1106662. doi: 10.3389/fphys.2023.1106662. eCollection 2023.
A physiological increase in cardiac workload results in adaptive cardiac remodeling, characterized by increased oxidative metabolism and improvements in cardiac performance. Insulin-like growth factor-1 (IGF-1) has been identified as a critical regulator of physiological cardiac growth, but its precise role in cardiometabolic adaptations to physiological stress remains unresolved. Mitochondrial calcium (Ca) handling has been proposed to be required for sustaining key mitochondrial dehydrogenase activity and energy production during increased workload conditions, thus ensuring the adaptive cardiac response. We hypothesized that IGF-1 enhances mitochondrial energy production through a Ca-dependent mechanism to ensure adaptive cardiomyocyte growth. We found that stimulation with IGF-1 resulted in increased mitochondrial Ca uptake in neonatal rat ventricular myocytes and human embryonic stem cell-derived cardiomyocytes, estimated by fluorescence microscopy and indirectly by a reduction in the pyruvate dehydrogenase phosphorylation. We showed that IGF-1 modulated the expression of mitochondrial Ca uniporter (MCU) complex subunits and increased the mitochondrial membrane potential; consistent with higher MCU-mediated Ca transport. Finally, we showed that IGF-1 improved mitochondrial respiration through a mechanism dependent on MCU-mediated Ca transport. In conclusion, IGF-1-induced mitochondrial Ca uptake is required to boost oxidative metabolism during cardiomyocyte adaptive growth.
心脏工作负荷的生理性增加会导致适应性心脏重塑，其特征为氧化代谢增加和心脏功能改善。胰岛素样生长因子-1（IGF-1）已被确定为生理性心脏生长的关键调节因子，但其在心脏代谢适应生理应激中的精确作用仍未明确。线粒体钙（Ca）处理被认为是在工作负荷增加的情况下维持关键线粒体脱氢酶活性和能量产生所必需的，从而确保适应性心脏反应。我们假设IGF-1通过一种依赖钙的机制增强线粒体能量产生，以确保适应性心肌细胞生长。我们发现，通过荧光显微镜估计，并间接通过丙酮酸脱氢酶磷酸化的降低，用IGF-1刺激可导致新生大鼠心室肌细胞和人胚胎干细胞衍生的心肌细胞中线粒体钙摄取增加。我们表明，IGF-1调节线粒体钙单向转运体（MCU）复合体亚基的表达并增加线粒体膜电位；这与更高的MCU介导的钙转运一致。最后，我们表明，IGF-1通过一种依赖MCU介导的钙转运的机制改善线粒体呼吸。总之，IGF-1诱导的线粒体钙摄取是心肌细胞适应性生长过程中促进氧化代谢所必需的。
