IGF1R Deficiency Modulates Brain Signaling Pathways and Disturbs Mitochondria and Redox Homeostasis.

Icíar López,Paula Moreira,Sergio Piñeiro-Hermida,Susana Cardoso,José Pichel

doi:10.3390/biomedicines9020158

Abstract

Insulin-like growth factor 1 receptor (IGF1R)-mediated signaling pathways modulate important neurophysiological aspects in the central nervous system, including neurogenesis, synaptic plasticity and complex cognitive functions. In the present study, we intended to characterize the impact of IGF1R deficiency in the brain, focusing on PI3K/Akt and MAPK/ERK1/2 signaling pathways and mitochondria-related parameters. For this purpose, we used 13-week-old UBC-CreERT2; Igf1rfl/fl male mice in which Igf1r was conditionally deleted. IGF1R deficiency caused a decrease in brain weight as well as the activation of the IR/PI3K/Akt and inhibition of the MAPK/ERK1/2/CREB signaling pathways. Despite no alterations in the activity of caspases 3 and 9, a significant alteration in phosphorylated GSK3β and an increase in phosphorylated Tau protein levels were observed. In addition, significant disturbances in mitochondrial dynamics and content and altered activity of the mitochondrial respiratory chain complexes were noticed. An increase in oxidative stress, characterized by decreased nuclear factor E2-related factor 2 (NRF2) protein levels and aconitase activity and increased H2O2 levels were also found in the brain of IGF1R-deficient mice. Overall, our observations confirm the complexity of IGF1R in mediating brain signaling responses and suggest that its deficiency negatively impacts brain cells homeostasis and survival by affecting mitochondria and redox homeostasis.

Highlights

Insulin-like growth factor type 1 receptor (IGF1R) is an important cellular modulator with essential roles in the regulation of growth, development and metabolism, as well as in cellular processes like proliferation, survival, cell migration and differentiation; affecting nearly every organ system in the body [1,2,3]
We found a significant increase of P13K (p110) protein levels (Figure 2a) as well as of the phosphorylation levels of intracellular serine/threonine kinase Akt, which transduces IGF1R signaling, in brain tissue from UBC-CreERT2; Igf1rfl/fl mutants (Figure 2b)
We have confirmed the importance and complexity of IGF1R signaling in the regulation of brain homeostasis

Summary

Introduction

Insulin-like growth factor type 1 receptor (IGF1R) is an important cellular modulator with essential roles in the regulation of growth, development and metabolism, as well as in cellular processes like proliferation, survival, cell migration and differentiation; affecting nearly every organ system in the body [1,2,3]. Biomedicines 2021, 9, 158 insulin receptor substrates (IRS) This activity ensues activation of downstream intracellular signaling pathways: (1) the canonical phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) and (2) the mitogen-activated protein (MAP) kinase ( called extracellular signal-regulated kinase; ERK), which transduce canonical ligand actions to control a number of essential biological outcomes [5,6,7]. Contradictions remain, and different transgenic animals have been developed to characterize and evaluate the involvement of the IGF1/IGF1R system in the central nervous system

Results

Discussion

Conclusion