Ischemia-Reperfusion Injury : Maintaining skeletal muscle function and vasomotor control

Abstract

In reconstructive surgery, ischemia-reperfusion (I-R) injury of skeletal muscle tissue occurs during replantations, free vascularized transfers of muscle flaps and following composite tissue allograft (CTA) transplantations. The latter is a newly emerging field and involves the allotransplantation of complex composite tissues from deceased donors. Complete and partial failures of free vascularized muscle flaps and replantations remain a significant clinical problem. The more frequent application of CTAs requires the design of a preservation strategy that prevents I-R injury and allows tissue banking with maintenance of cellular function. Full recovery following I-R insults requires both skeletal muscle - and microvascular integrity. The hamster retractor muscle model (RET) is unique in that the muscle can be exteriorized while preserving its vascular supply, enabling in vivo muscle force production to be monitored concomitant with microvascular responses of the peripheral circulation. This model has provided novel insights into the regulation of skeletal muscle blood flow by “ascending vasodilation” (AVD) during contractile activity. AVD entails the ascend of the initial vasodilation of the intramuscular arteriolar networks to the proximally located “feed arteries”. These proximal vessels were shown to play a key role in the vasomotor control of skeletal muscle. The work described in this thesis reports the first in vivo evaluation of ascending vasodilation (AVD) and contractile muscle function following I-R. Both contractile muscle function and AVD of RET feed arteries in response to contractile activity are severely affected by a relatively short period of I-R (1 hour-1 hour) at 37C. The observed reduction in AVD is based upon attenuated initiation of vasodilation within the arteriolar network of the RET. Ca2+ overload is the main cause for the observed derangement of contractile function at 37C, whereas the formation of the highly reactive hydroxyl radical (OH?) is not a causative factor. Also, the deficit in initiation of AVD can not be attributed to the formation of OH?. As concluded from experiments performed at 21C, reduction of metabolic turnover or decreased formation of other reactive oxygen species (ROS) than OH? contribute to the maintenance of skeletal muscle function and vasomotor control following I-R. In this thesis the RET was also used in the context of developing CTA preservation strategies. Following cold storage (16 hours at 4C) of the isolated RET, formation of ROS turned out to be a major reason for loss in contractile muscle function, while Ca2+ overload did not contribute to this dysfunction. The last chapter provides essential anatomical information concerning the RET and its vascular pedicle. It is demonstrated that the RET can be isolated on its thoracodorsal pedicle and can be used as a free flap model for future evaluation of the effect of preservation strategies and transplantation on skeletal muscle microcirculation and contractile function.