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

P. Sanchez-Aguilera, C. Lopez-Crisosto, I. Norambuena-Soto, C. Penannen, J.M. Zhu, N. Bomer, M.F. Hoes, P. van der Meer, M. Chiong, B.D. Westenbrink*, S. Lavandero*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 (Ca2+) 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 Ca2+-dependent mechanism to ensure adaptive cardiomyocyte growth. We found that stimulation with IGF-1 resulted in increased mitochondrial Ca2+ 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 Ca2+ uniporter (MCU) complex subunits and increased the mitochondrial membrane potential; consistent with higher MCU-mediated Ca2+ transport. Finally, we showed that IGF-1 improved mitochondrial respiration through a mechanism dependent on MCU-mediated Ca2+ transport. In conclusion, IGF-1-induced mitochondrial Ca2+ uptake is required to boost oxidative metabolism during cardiomyocyte adaptive growth.
Original languageEnglish
Article number1106662
Number of pages10
JournalFrontiers in physiology
Volume14
Issue number1
DOIs
Publication statusPublished - 8 Feb 2023

Keywords

  • insulin-like growth factor 1 (IGF-1)
  • MCU complex
  • mitochondrial calcium handling
  • physiological cardiac hypertrophy
  • neonatal rat ventricular myocytes (NRVMs)
  • human embryonic stem cell derived-cardiomyocytes (hES-CMs)
  • CALCIUM UNIPORTER
  • HEART-FAILURE
  • MCUR1
  • METABOLISM
  • ACTIVATION
  • REGULATOR
  • CCDC90A
  • DISEASE
  • STRESS

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