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

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.

ATPIF-1 knockout attenuates mitochondrial mPTP opening but does not diminish cardiac ischemic/reperfusion injury.

“…Consequently, inhibiting ATPIF-1 has been suggested as a viable approach to postpone or prevent detrimental metabolic changes following a cardiac injury (12). Mitochondrial Ca 2+ concentrations exhibit a homeostatic range that enables mitochondria to enhance NADH generation and ATP synthesis (23). Nevertheless, Ca 2+ concentrations exceeding the physiological range initially trigger a reversible and transient low-conductance mPTP opening, which prevents the accumulation of Ca 2+ and ROS.…”

Adult Human Heart ECM Improves Human iPSC-CM Function via Mitochondrial and Metabolic Maturation

“…Fig. 1B), which in turn promotes mesoderm formation for an efficient cardiac differentiation [51] and boosts mitochondrial function hence oxidative metabolism during cardiomyocyte adaptive growth by a Ca2+ uptake-dependent mechanism in cultured human and rat CMs [60], respectively.…”

“…Fig. 1B), which in turn promotes mesoderm formation for an efficient cardiac differentiation [51] and boosts mitochondrial function hence oxidative metabolism during cardiomyocyte adaptive growth by a Ca2+ uptake-dependent mechanism in cultured human and rat CMs [60], respectively. Similarly, apolipoproteins were associated with enhanced cardiac differentiation of ESCs and iPSCs and promoted maturation of the Ca2+ handling properties of ESC-derived CMs via the BMP4/SMAD signaling pathway [61].…”

Factor de crecimiento análogo a insulina-1 y cardiotrofina-1 inducido por ejercicio y su relación con hipertrofia miocárdica en maratonistas

“…Además, la sobreexpresión del receptor de IGF 1 en los cardiomiocitos también induce un aumento de su tamaño, los protege de la apoptosis y mejoran la función sistólica 24 . Los efectos hipertróficos de IGF-1 también se pueden observar en cardiomiocitos humanos 25 . Nuestros resultados muestran que los atletas que aumentan los niveles plasmáticos de IGF-1 por el ejercicio presentan un mayor volumen ventricular en sístole y en diástole, respecto a los que no aumentan o disminuyen sus niveles de IGF-1.…”