Ischemic‐preconditioning does not prevent neuromuscular dysfunction after ischemia–reperfusion injury

Abstract

The primary purpose of this study was to evaluate ischemic‐preconditioning (IPC) as a means of improving tolerance to ischemia–reperfusion (IR) stress on neuromuscular function. A secondary objective was to isolate the area of injury within the neuromuscular unit responsible for contractile dysfunction after IR injury. Twenty‐eight male rabbits were randomly assigned to four groups (sham, IPC only, sustained ischemia only, IPC and sustained ischemia). The IPC protocol consisted of three cycles of 10 min of tourniquet‐induced ischemia (125 mmHg) followed by 10 min of reperfusion. Sustained ischemia was induced by 350 mmHg external compression for 2 h. Peak tetanic tension of the tibialis anterior (TA) muscle was evaluated 48 h after the tourniquet protocol by both peroneal nerve and direct muscle stimulation, with and without pharmacologic neuromuscular junction blockade. Animals subjected to combined IPC and sustained ishemia had an equivalent loss of contractile force to those undergoing sustained ischemia alone. Two hours of tourniquet‐induced ischemia resulted in marked dysfunction of the TA neuromuscular unit when evaluated by peroneal nerve stimulation (p < 0.0001). Isolation of the TA muscle from the peroneal nerve with direct muscle stimulation and neuromuscular junction blockade preserved muscle function after 3 h of ischemia. In our model, these results clearly demonstrate that IPC provides no significant protective effect from IR injury to either nerve or muscle function in our model. In addition, nerve or neuromuscular junction injury, rather than muscle damage, is identified as primarily responsible for IR‐related muscle dysfunction. © 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.

Treatment of Tourniquet-Induced Ischemia Reperfusion Injury with Muscle Progenitor Cells

“…Others have reported a decrease in specific force following acute IRI [31,43]. In our study, the 70% loss in absolute muscle force in Veh controls resulted from the 20% loss in muscle mass and 60% loss in muscle-specific force; thus the observed deficits in force production are primarily attributable to the loss of specific force.…”

Mitochondrial protein S-nitrosation protects against ischemia reperfusion-induced denervation at neuromuscular junction in skeletal muscle

“…3a), providing the first evidence of motor nerve. Ischemic-preconditioning has previously shown not effective in preventing neuromuscular dysfunction induced by IR [9,51]. Conversely, force production induced by direct muscle stimulation was reduced similarly in saline-, MitoNAP- and MitoSNO-treated hindlimb muscles compared to the sham control (Fig.…”

“…We performed a 28-day longitudinal study, in which we measured the maximal tetanic force production of the planter flexors in vivo via nerve stimulation or direct muscle stimulation. These protocols provide insight into neuromuscular transmission and force generating capacity of the muscle, respectively [9,42]. In un-injured mice (sham), force production resulting from nerve and muscle stimulations was indistinguishable (Fig.…”

“…In addition to muscle weakness and atrophy [5,6], IR injury can cause irreversible nerve and NMJ damage [7,8], all of which hinder functional recovery of the affected skeletal muscle. However, we know little about the underlying mechanism(s) of IR-induced neuromuscular damage, and hence there is currently no reliable and effective intervention [9–11]. …”

Calcium dependence of damage to mouse motor nerve terminals following oxygen/glucose deprivation

“…For example, in rat hind limbs subjected to 2 h of tourniquet ischemia and then examined 1–28 days later, electron microscopic analysis detected no changes in axons, Schwann cells or muscle fibers, but did detect multiple signs of degeneration in motor nerve terminals, including disruption of the presynaptic membrane, the appearance of vacuoles, and degeneration of mitochondria (Makitie and Teravainen, 1977; Tombol et al, 2002). Functional measurements also indicate that the neuromuscular junction is a major site of I/R injury (Eastlack et al, 2004). Baxter et al (2008) found that mouse motor nerve terminals are also selectively vulnerable to hypoxia/reoxygenation, an in vitro model of I/R stress.…”