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Establishing A Murine Model Of Muscle Atrophy In Chronic Nerve Compression
Jordan Burgess, B.A.1,2, Zhen Wang, M.D.1,2, James Chang, M.D.1,2, Paige M. Fox, M.D., Ph.D.1,2.
1Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA, 2Stanford University School of Medicine, Stanford, CA, USA.

PURPOSE: Chronic compression neuropathies are characterized by progressive demyelination, impaired nerve conduction velocity, and muscle atrophy. Previous studies have established a model of chronic nerve compression (CNC) in mice, however these studies did not investigate changes to the muscle. We aim to establish a mouse model of muscle atrophy in CNC and to determine the mechanism and timing of muscle changes correlated with changes in nerve conduction speed (NCS), compound motor action potential (CMAP) amplitude, nerve myelination, and axonal integrity.
METHODS: CNC was induced by placing a silastic tube around the sciatic nerve with the contralateral limb as an internal control. At 6, 8, and 12 weeks, NCS and CMAP amplitude were assessed, and the gastrocnemius (GN), tibialis anterior (TA), and sciatic nerve were harvested bilaterally. Muscle weight, body weight, muscle fiber size using wheat germ agglutin staining, axon integrity using neurofilament H (NFH) staining, and myelination using myelin protein zero (MPZ) staining were measured. Data are expressed as fold change relative to control. Differences were considered significant at p<0.05.
RESULTS: GN and TA muscle weight were significantly reduced relative to control at 6, 8, and 12 weeks compression. GN muscle weight was significantly reduced 0.89 0.08, 0.82 0.08, and 0.92 0.01 fold at 6, 8 and 12 weeks, respectively. TA muscle weight was significantly reduced 0.95 0.04, 0.80 0.07, and 0.84 0.01 fold at 6, 8 and 12 weeks, respectively. Across time-points, differences in TA muscle weight were significant at p=0.002. In addition, TA muscle fiber cross-sectional area was reduced 0.95 0.15 fold at 6 weeks, 0.77 0.03 fold at 8 weeks, and 0.71 0.09 fold at 12 weeks. Across time-points, differences in TA muscle fiber cross-sectional area were significant at p=0.012.
Nerve conduction speed and CMAP amplitude were also reduced relative to control. Nerve conduction speed was reduced 0.74 0.15, 0.71 0.07, and 0.84 0.09 fold at 6, 8 and 12 weeks, respectively. Results were significant at 6 and 8 weeks. CMAP amplitude was reduced 0.88 0.26, 0.73 0.16, and 0.56 0.16 fold at 6, 8 and 12 weeks, respectively. Results were significant at 8 and 12 weeks.
Lastly, NFH fluorescence intensity was reduced 0.43 0.14, and 0.63 0.09 fold at 8 and 12 weeks, respectively. MPZ fluorescence intensity was reduced 0.37 0.09, and 0.37 0.10 fold at 8 and 12 weeks, respectively. Data are summarized in Table 1.
CONCLUSION: The murine model of CNC demonstrates reduced muscle weight and decreased muscle fiber size over time relative to control. Muscle atrophy correlates with slower nerve conduction velocity, reduced axon integrity, and demyelination. These findings establish a mouse model of muscle atrophy in CNC that will allow us to determine the mechanism of muscle atrophy and develop new therapies for compression neuropathies.


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