Disparate Central and Peripheral Effects of Circulating IGF-1 Deficiency on Tissue Mitochondrial Function

Gavin Pharaoh,Pavithra Premkumar,Shylesh Bhaskaran,Holly Van Remmen,Julie Farley,Michael Kinter,Daniel Owen,Nicole Ashpole,Alexander Yeganeh,Sreemathi Logan

doi:10.1007/s12035-019-01821-4

Abstract

Age-related decline in circulating levels of insulin-like growth factor (IGF)-1 is associated with reduced cognitive function, neuronal aging, and neurodegeneration. Decreased mitochondrial function along with increased reactive oxygen species (ROS) and accumulation of damaged macromolecules are hallmarks of cellular aging. Based on numerous studies indicating pleiotropic effects of IGF-1 during aging, we compared the central and peripheral effects of circulating IGF-1 deficiency on tissue mitochondrial function using an inducible liver IGF-1 knockout (LID). Circulating levels of IGF-1 (~ 75%) were depleted in adult male Igf1f/f mice via AAV-mediated knockdown of hepatic IGF-1 at 5 months of age. Cognitive function was evaluated at 18 months using the radial arm water maze and glucose and insulin tolerance assessed. Mitochondrial function was analyzed in hippocampus, muscle, and visceral fat tissues using high-resolution respirometry O2K as well as redox status and oxidative stress in the cortex. Peripherally, IGF-1 deficiency did not significantly impact muscle mass or mitochondrial function. Aged LID mice were insulin resistant and exhibited ~ 60% less adipose tissue but increased fat mitochondrial respiration (20%). The effects on fat metabolism were attributed to increases in growth hormone. Centrally, IGF-1 deficiency impaired hippocampal-dependent spatial acquisition as well as reversal learning in male mice. Hippocampal mitochondrial OXPHOS coupling efficiency and cortex ATP levels (~ 50%) were decreased and hippocampal oxidative stress (protein carbonylation and F2-isoprostanes) was increased. These data suggest that IGF-1 is critical for regulating mitochondrial function, redox status, and spatial learning in the central nervous system but has limited impact on peripheral (liver and muscle) metabolism with age. Therefore, IGF-1 deficiency with age may increase sensitivity to damage in the brain and propensity for cognitive deficits. Targeting mitochondrial function in the brain may be an avenue for therapy of age-related impairment of cognitive function. Regulation of mitochondrial function and redox status by IGF-1 is essential to maintain brain function and coordinate hippocampal-dependent spatial learning. While a decline in IGF-1 in the periphery may be beneficial to avert cancer progression, diminished central IGF-1 signaling may mediate, in part, age-related cognitive dysfunction and cognitive pathologies potentially by decreasing mitochondrial function.

Highlights

Aging is associated with reductions in mitochondrially derived energy production [1], global increases in oxidative load, and a concomitant decline in correlates of cognitive function, neuronal and astroglial function [4,5,6]
Cognitive testing and further analyses on the brain were conducted at 18 months based on previous studies that showed a decline in hippocampal neurogenesis by 18 months which persisted up to 28 months that was ameliorated by insulin-like growth factor (IGF)-1 infusion [43]
Mitochondrial functional testing on muscle and fat tissue were conducted at approximately 24 months, since previous studies on aged mice and with Insulin-like growth factor-1 (IGF-1) transgene expression in skeletal muscle have typically looked at 22–24-month mice [44]

Summary

Introduction

Aging is associated with reductions in mitochondrially derived energy production [1], global increases in oxidative load (reviewed by [2, 3]), and a concomitant decline in correlates of cognitive function, neuronal and astroglial function [4,5,6]. Insulin-like growth factor-1 (IGF-1) is a potent neurotrophic factor that is abundantly expressed in the central nervous system during embryonic development and peaks during puberty, a period of rapid growth and development [9]. IGF-1 is produced and secreted into the bloodstream primarily by the liver in response to growth hormone (GH) secreted by the anterior pituitary. IGF-1 produced by the liver is transported by IGF-1 binding proteins (IGFBP) and crosses the blood-brain barrier. IGF-1 ligand binding to its cognate receptor, insulin-like growth factor receptor (IGFR), induces conformational changes that initiate receptor autophosphorylation of the intracellular kinase domains [12] that activate downstream signaling cascades including the PI3K/AKT and MAPK pathways that drive cell survival and growth [13]

Methods

Results

Conclusion