Role of aging in nerve and muscle changes after chronic nerve compression in mice

Chronic nerve compression (CNC) impacts over one million Americans annually, causing substantial functional and economic burdens. Despite its prevalence, the translational relevance of murine CNC models is limited by the use of young animals and a lack of studies investigating post-decompression recovery. This study aims to characterize CNC in aged mice compared to young mice and assess nerve and muscle recovery following surgical release in aged animals.

Young (20-week) and aged (67-week) male C57BL/6 J mice underwent 16 weeks of sciatic nerve compression. A subset of aged mice received surgical decompression, followed by a 4-week recovery. Electrophysiological, histological, and molecular analyses were performed on nerve and muscle tissues to evaluate changes induced by CNC and decompression.

CNC induced demyelination in both young and aged mice, with aged mice exhibiting greater axonal atrophy. Young mice muscle demonstrated increased expression of atrophic and fibrotic markers such as Atrogin1, MuRF1, and α-SMA. Conversely, we observed increased expression of MyoD and MyoG myogenic markers in aged mice muscle, correlating with increased average muscle fiber cross-sectional area. In aged mice, surgical release restored electrophysiological parameters, normalized histological features, and reversed molecular gene adaptations.

The molecular and structural responses to CNC in affected muscle differ with age, with aged mice demonstrating a shift from atrophic to myogenic pathways compared to young mice. Surgical release effectively mitigates CNC-induced deficits, emphasizing its therapeutic value. This study highlights the importance of age-appropriate models for understanding CNC pathophysiology and recovery dynamics.