Link between the protective effect of ischemic preconditioning in skeletal muscles and the substance that triggers hibernation

A phenomenon known as ischemic preconditioning (IP), in which blood flow to muscle is reduced and then restored, has previously been shown to increase muscle function, especially in the heart.

A new study published online June 6, 2005 in Muscle & Nerve explores the link between the protective effect of IP in skeletal muscles and the substance that triggers hibernation. The journal is available online via Wiley InterScience.

During certain types of vascular or reconstructive surgery, it is sometimes necessary to block blood flow, which may cause tissue damage. This problem might potentially be alleviated if a pharmacological substance was able to achieve IP. Hibernation in mammals is thought to confer cardiac benefits similar to IP. Researchers led by Jinback Hong, Ph.D. of the department of biomedical engineering at the University of Minnesota in Minneapolis, MN, set out to explore whether pretreatment with the chemical that induces hibernation (hibernation induction trigger or HIT) would have the same protective effect as IP in skeletal muscles and the mechanism by which this effect might occur. The study involved removing muscle tissue from 77 pigs, and subjecting it to hypoxia (a reduction of oxygen supply) for 90 minutes, followed by 120 minutes of reoxygenation. The muscles were then divided into several groups that were treated with plasma from hibernating woodchucks (HWP), plasma from woodchucks active in the summer (SAWP), HWP plus naloxone (an opiate receptor antagonist), HWP plus potassium channel blocker, and various control groups. After 30 minutes and 120 minutes of reoxygenation, the HWP group showed significantly more muscle activity, as measured by twitch force, than the other groups. The HWP group was also not significantly different than a control group that was not subjected to hypoxia.

In discussing the effect of serum taken from a hibernator on the skeletal muscles of a nonhibernator, the authors state: "Such an acute response may also suggest that preconditioning with HIT or a similar agonist could be employed for humans in certain clinical situations, such as during vascular and musculoskeletal reconstructive surgery (e.g., a total knee replacement)." They note that since the HWP group recovered to the same level of force as the group that was not exposed to hypoxia, the protective factors in the plasma of the hibernating woodchucks safeguarded the muscle quite optimally.

One of the pathways that has been identified in IP and the subsequent protection of muscle is the opening of potassium channels, which in heart muscle is associated with the accumulation of opioids. The researchers attempted to determine if this same mechanism was involved in HIT's protective effects. They administered a potassium channel blocker with the HWP, using dimethylsulfoxide (DMSO) as a solvent. However, since DMSO is itself associated with a decreased twitch force, the results were inconclusive. When the opiate receptor antagonist naloxone was used, the results showed that it weakened the effects of HWP, suggesting that HWP works in part through some type of action on opioid receptors.

The researchers conclude that "pharmacological preconditioning of skeletal muscle to reduce necrosis [tissue death] associated with hypoxia/reperfusion could provide clinical benefits such as improved recovery time and fewer postsurgical complications for patients who have endured prolonged regional skeletal muscle ischemia."

http://www.interscience.wiley.com/journal/mus