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Abnormal Muscle Spindle Innervation and Large-Fiber Neuropathy in Diabetic Mice

¹Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160
²Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109

Objective: Large-fiber DPN leads to balance and gait abnormalities, placing patients at risk for falls. Large sensory axons innervating muscle spindles provide feedback for balance and gait and, when damaged, can cause altered sensorimotor function. This study aimed to determine whether symptoms of large-fiber DPN in type 1 and 2 diabetic mouse models are related to alterations in muscle spindle innervation. In addition, diabetic mice were treated with insulin to assess whether sensorimotor and spindle deficits were reversible.

Research Design and Methods: Behavioral assessments were performed in untreated and treated streptozotocin (STZ)-injected C57BL/6 mice to quantitate diabetes-induced deficits in balance and gait. Quantification of Ia axon innervation of spindles was carried out using immunohistochemistry and confocal microscopy on STZ-injected C57BL/6 and db/db mice.

Results: STZ-injected C57BL/6 mice displayed significant and progressive sensorimotor dysfunction. Analysis of Ia innervation patterns of diabetic C57BL/6 spindles revealed a range of abnormalities suggestive of Ia axon degeneration and/or regeneration. The multiple abnormal Ia fiber morphologies resulted in substantial variability in axonal width and inter-rotational distance (IRD). Likewise, db/db mice displayed significant variability in their IRDs compared to db+ mice, suggesting that damage to Ia axons occurs in both type 1 and 2 models. Insulin treatment improved behavioral deficits and restored Ia fiber innervation comparable to nondiabetic mice.

Conclusions: Similar to small fibers, Ia axons are vulnerable to diabetes and their damage may contribute to balance and gait deficits. In addition, these studies provide a novel method to assay therapeutic interventions designed for diabetes-induced large-fiber dysfunction.

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