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Modulation of Microglia by Voluntary Exercise or CSF1R Inhibition Prevents Age-Related Loss of Functional Motor Units
Elisa Giorgetti1, Moh Panesar1, Yunyu Zhang2
1Musculoskeletal Diseases Area, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
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.
Insights
Aging causes motor neuron loss, impairing muscle function. Counteracting neurotoxic microglia in the spinal cord can maintain motor units (MUs) and prevent muscle decline in aged mice.
Area of Science:
- Neuroscience
- Aging Research
- Immunology
Background:
- Age-related loss of motor neuron innervation impairs neuromuscular function.
- The exact mechanisms driving this decline are not fully understood.
- Microglial activation in the aged spinal cord is implicated.
Purpose of the Study:
- To investigate the role of spinal cord microglia in age-related motor unit loss.
- To determine if interventions targeting microglia can preserve neuromuscular function.
Main Methods:
- Utilized aged mice models.
- Employed motor unit number estimation (MUNE) to assess innervation.
- Analyzed gene expression changes in the spinal cord.
- Investigated effects of voluntary exercise and CSF1R inhibition (microglia depletion).
Main Results:
- Innervation changes (MUNE decline) precede functional muscle loss in aged mice.
- Spinal cord gene expression shows microglial activation and neuronal remodeling.
- Voluntary exercise prevented motor unit loss and reversed microglial activation.
- CSF1R inhibition prevented MUNE decline and neuromuscular junction disruption.
Conclusions:
- Age-related changes in spinal cord microglia contribute to neuromuscular decline.
- Targeting and removing aged, neurotoxic microglia can prevent or reverse motor unit loss and preserve neuromuscular function.
