Hindlimb immobilization induces insulin resistance and elevates mitochondrial ROS production in the hippocampus of female rats.

Autor:	Kerr NR; Department of Biomedical Sciences, University of Missouri, Columbia, Missouri, United States., Mossman CW; Veterinary Medical Diagnostic Laboratory, University of Missouri, Columbia, Missouri, United States., Chou CH; Department of Biomedical Sciences, University of Missouri, Columbia, Missouri, United States., Bunten JM; Department of Biomedical Sciences, University of Missouri, Columbia, Missouri, United States., Kelty TJ; Department of Biomedical Sciences, University of Missouri, Columbia, Missouri, United States.; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States.; NextGen Precision Health, University of Missouri, Columbia, Missouri, United States., Childs TE; Department of Biomedical Sciences, University of Missouri, Columbia, Missouri, United States., Rector RS; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States.; NextGen Precision Health, University of Missouri, Columbia, Missouri, United States.; Research Service, Harry S. Truman Memorial Veterans Medical Center, University of Missouri, Columbia, Missouri, United States.; Department of Medicine, University of Missouri, Columbia, Missouri, United States., Arnold WD; NextGen Precision Health, University of Missouri, Columbia, Missouri, United States.; Department of Physical Medicine and Rehabilitation, University of Missouri, Columbia, Missouri, United States.; Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri, United States.; Department of Neurology, University of Missouri, Columbia, Missouri, United States., Grisanti LA; Department of Biomedical Sciences, University of Missouri, Columbia, Missouri, United States., Du X; Department of Biomedical Sciences, University of Missouri, Columbia, Missouri, United States.; Veterinary Medical Diagnostic Laboratory, University of Missouri, Columbia, Missouri, United States., Booth FW; Department of Biomedical Sciences, University of Missouri, Columbia, Missouri, United States.; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States.; Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri, United States.; Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, United States.
Jazyk:	angličtina
Zdroj:	Journal of applied physiology (Bethesda, Md. : 1985) [J Appl Physiol (1985)] 2024 Sep 01; Vol. 137 (3), pp. 512-526. Date of Electronic Publication: 2024 Jul 04.
DOI:	10.1152/japplphysiol.00234.2024
Abstrakt:	Alzheimer's disease (AD) is the fifth leading cause of death in older adults, and treatment options are severely lacking. Recent findings demonstrate a strong relationship between skeletal muscle and cognitive function, with evidence supporting that muscle quality and cognitive function are positively correlated in older adults. Conversely, decreased muscle function is associated with a threefold increased risk of cognitive decline. Based on these observations, the purpose of this study was to investigate the negative effects of muscle disuse [via a model of hindlimb immobilization (HLI)] on hippocampal insulin sensitivity and mitochondrial function and identify the potential mechanisms involved. HLI for 10 days in 4-mo-old female Wistar rats resulted in the following novel findings: 1 ) hippocampal insulin resistance and deficits in whole body glucose homeostasis, 2 ) dramatically increased mitochondrial reactive oxygen species (ROS) production in the hippocampus, 3 ) elevated markers for amyloidogenic cleavage of amyloid precursor protein (APP) and tau protein in the hippocampus, 4 ) and reduced brain-derived neurotrophic factor (BDNF) expression. These findings were associated with global changes in iron homeostasis, with muscle disuse producing muscle iron accumulation in association with decreased serum and whole brain iron levels. We report the novel finding that muscle disuse alters brain iron homeostasis and reveal a strong negative correlation between muscle and brain iron content. Overall, HLI-induced muscle disuse has robust negative effects on hippocampal insulin sensitivity and ROS production in association with altered brain iron homeostasis. This work provides potential novel mechanisms that may help explain how loss of muscle function contributes to cognitive decline and AD risk. NEW & NOTEWORTHY Muscle disuse via hindlimb immobilization increased oxidative stress and insulin resistance in the hippocampus. These findings were in association with muscle iron overload in connection with iron dysregulation in the brain. Overall, our work identifies muscle disuse as a contributor to hippocampal dysfunction, potentially through an iron-based muscle-brain axis, highlighting iron dysregulation as a potential novel mechanism in the relationship between muscle health, cognitive function, and Alzheimer's disease risk.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu