Esketamine exerts a protective effect against skeletal muscle injury induced by hindlimb ischemia-reperfusion in mice by regulating autophagy

Tourniquet-associated lower limb ischemia-reperfusion can induce skeletal muscle inflammation, edema, and early functional impairment, in which autophagy dysregulation may be involved. The present study was designed to investigate the effects of esketamine (ESK) on skeletal muscle injury following lower limb ischemia-reperfusion in mice and its relationship with autophagy regulation. A mouse model of left hindlimb ischemia for 3 hours followed by 24 hours of reperfusion was established, and changes in hindlimb perfusion, functional outcomes, tissue injury, inflammatory response, and autophagy-related markers were examined after intervention with ESK alone or in combination with chloroquine phosphate (CQ). The results showed that ESK attenuated the abnormally elevated perfusion after reperfusion, improved motor performance and partial muscle contractile function, yet exerted limited effects on mechanical pain threshold and nerve stimulation-induced muscle contraction. Concurrently, ESK alleviated histological damage, edema, and sarcolemmal integrity disruption in the gastrocnemius muscle, reduced serum Tumor Necrosis Factor-alpha and Interleukin-6 levels, and downregulated the expression of several inflammation-related genes. With respect to autophagy, ESK increased the microtubule-associated protein 1 light chain 3 II/I ratio while decreasing sequestosome 1 levels and the phosphorylated mechanistic target of rapamycin/total mechanistic target of rapamycin ratio; these protective effects were partially abrogated by CQ. Collectively, these findings indicate that ESK mitigates acute-phase skeletal muscle injury and improves selected early functional outcomes after lower limb ischemia-reperfusion in mice, and that its protective actions may be associated with suppression of inflammation and modulation of autophagy.