51. Modulation of Microglia by Voluntary Exercise or CSF1R Inhibition Prevents Age-Related Loss of Functional Motor Units.
- Author
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Giorgetti E, Panesar M, Zhang Y, Joller S, Ronco M, Obrecht M, Lambert C, Accart N, Beckmann N, Doelemeyer A, Perrot L, Fruh I, Mueller M, Pierrel E, Summermatter S, Bidinosti M, Shimshek DR, Brachat S, and Nash M
- Subjects
- Aging pathology, Animals, Cell Line, Databases, Genetic, Humans, Induced Pluripotent Stem Cells, Macrophages, Male, Mice, Mice, Inbred C57BL, Microglia enzymology, Microglia physiology, Motor Neurons cytology, Motor Neurons pathology, Muscle, Skeletal metabolism, Muscle, Skeletal physiopathology, Neuromuscular Junction metabolism, Neuronal Plasticity genetics, RNA-Seq, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor genetics, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Spinal Cord enzymology, Spinal Cord metabolism, Spinal Cord physiopathology, Aging metabolism, Microglia metabolism, Motor Neurons metabolism, Physical Conditioning, Animal physiology, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor antagonists & inhibitors
- Abstract
Age-related loss of skeletal muscle innervation by motor neurons leads to impaired neuromuscular function and is a well-established clinical phenomenon. However, the underlying pathogenesis remains unclear. Studying mice, we find that the number of motor units (MUs) can be maintained by counteracting neurotoxic microglia in the aged spinal cord. We observe that marked innervation changes, detected by motor unit number estimation (MUNE), occur prior to loss of muscle function in aged mice. This coincides with gene expression changes indicative of neuronal remodeling and microglial activation in aged spinal cord. Voluntary exercise prevents loss of MUs and reverses microglia activation. Depleting microglia by CSF1R inhibition also prevents the age-related decline in MUNE and neuromuscular junction disruption, implying a causal link. Our results suggest that age-related changes in spinal cord microglia contribute to neuromuscular decline in aged mice and demonstrate that removal of aged neurotoxic microglia can prevent or reverse MU loss., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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