IGF-1 boosts mitochondrial function by a Ca2+ uptake-dependent mechanism in cultured human and rat cardiomyocytes

• Published in: Frontiers in physiology 2023-02, Vol.14, p.1106662-1106662
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: human embryonic stem cell derived-cardiomyocytes (hES-CMs); insulin-like growth factor 1 (IGF-1); MCU complex; mitochondrial calcium handling; neonatal rat ventricular myocytes (NRVMs); physiological cardiac hypertrophy; Physiology
• ISSN: 1664-042X; 1664-042X
• DOI: 10.3389/fphys.2023.1106662

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 2+ ) 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 2+ -dependent mechanism to ensure adaptive cardiomyocyte growth. We found that stimulation with IGF-1 resulted in increased mitochondrial Ca 2+ 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 2+ uniporter (MCU) complex subunits and increased the mitochondrial membrane potential; consistent with higher MCU-mediated Ca 2+ transport. Finally, we showed that IGF-1 improved mitochondrial respiration through a mechanism dependent on MCU-mediated Ca 2+ transport. In conclusion, IGF-1-induced mitochondrial Ca 2+ uptake is required to boost oxidative metabolism during cardiomyocyte adaptive growth.