Establishing a Murine Model of Muscle Changes in Chronic Nerve Compression

Abstract

Purpose

We aimed to build upon a previously validated model of early chronic nerve compression (CNC) by evaluating changes in gross muscle weight, muscle gene expression, and muscle function, and correlating the mechanism and timing of muscle- and nerve related changes.

Methods

Chronic nerve compression was induced by placing a Silastic tube around the sciatic nerve with the contralateral limb as control. At 6, 8, and 12 weeks of compression, gait analysis, muscle force measurements, and electrodiagnostics (EDX) were performed, and the sciatic nerve, tibialis anterior (TA), extensor digitorum longus (EDL), and gastrocnemius were harvested. Muscle weight (MW), cross-sectional area (CSA), g-ratio, axon area, and axon density were measured. Reverse transcripton polymerase chain reaction of TA+EDL muscle was performed. Genes assayed included atrogenes (Foxo-3, Atrogin-1, and MuRF1), markers of myogenesis (MyoD and MyoG), fatty acid synthase, type-I collagen (Col1a1), and inflammatory markers (tumor necrosis factor-α and interleukin-1β).

Results

At 6 weeks, we observed a maximum 30.8% decrease in nerve conduction speed. G-ratio was increased 14.4% at 8 weeks, and at all time points, we observed a 25%–26% decrease in axon area. At 12 weeks, we observed a 10.4% decrease in TA+EDL MW, and at 8 weeks, CSA was reduced 13.9%. At 8 weeks, expression of atrogenes was increased 2–3-fold implying ongoing atrophy. MyoD/MyoG expression was reduced 0.3 times, and fatty acid synthase, type-1 collagen, and inflammatory marker expression was increased 1.3-, 1.4-, and >2-fold, respectively. There were no clinically important differences in gait analysis or muscle force measurement between compressed and control limbs at any time-point.

Conclusions

The murine model of muscle changes in CNC demonstrates reduced nerve conduction speed, demyelination, and a shift in axon size consistent with early CNC. Changes in MW, CSA, and gene expression occur in the absence of significant differences in muscle function.

Clinical relevance

These findings establish a mouse model of early muscle changes in CNC that can be used to investigate interventions to reduce or delay muscle changes in compression neuropathies.