Functional Salvage of Ischemic Myopathy at the Neuromuscular Junction Level: A Mouse Model Study on Prolonged Muscle Ischemia in the Upper Limb

Ischemic myopathy in the upper limb may develop progressively in cases of peripheral arterial disease or acutely following traumatic vascular injuries. Prolonged ischemia can lead to catastrophic damage to distal muscles, with a significant risk of irreversible motor function loss. It is hypothesized that the neuromuscular junction (NMJ) sustains substantial damage beyond a critical threshold of arterial ischemia. Furthermore, concomitant upstream nerve injuries may exacerbate NMJ degeneration, potentially resulting in permanent dysfunction. This study aims to evaluate the NMJ-level changes in target muscles and investigate the impact of nerve injury and repair, with a particular focus on the potential benefits of the supercharge end-to-side (SETS) nerve transfer technique.A mouse forelimb ischemia model was created by clamping the brachial artery and ablating collateral vessels. The first aim assessed NMJ changes with increasing ischemia time. The second investigated the impact of ischemia on muscle reinnervation after transection and repair of the median nerve. Lastly, the ulnar nerve was used for SETS to the distal median nerve following nerve repair to evaluate its effect on muscle recovery. Functional grip tests, electrophysiological assessments, and immunohistochemical analyses were performed.Prolonged ischemia significantly decreased CMAP and grip strength, with markedly declined after 8 hours of prolonged arterial ischemia. When the upstream median nerve was cut and repaired, NMJ innervation of the target muscle dropped significantly at 12 hours, with fully innervated NMJs reduced to 27 to 39% compared with 67 to 72% at 4 to 8 hours (control = 81%). SETS transfers significantly improved CMAP, grip strength, and NMJ innervation, particularly in the 12-hour ischemia group.Prolonged ischemia leads to severe NMJ degeneration within the target muscle, with 8 hours being the critical time point at limb ischemia, and 12 hours being the time point after ischemia and nerve injury. As an alternative to limb amputation or muscle loss, SETS nerve transfer to augment the innervating median nerve can initiate partial NMJ innervation within the remaining target muscles to attempt to restore functional capacity.