Recovery Of Skeletal Muscle Function Research Articles

Leukemia inhibitory factor enhances the regeneration of transected rat sciatic nerve and the function of reinnervated muscle

The cytokine leukemia inhibitory factor (LIF) favors the survival and growth of axons in vitro and in vivo. Fibronectin has been shown to enhance nerve regeneration when added in combination with various growth factors including LIF. The goal of this study was to evaluate the effect of LIF plus fibronectin on the regeneration of transected nerve and functional recovery of reinnervated skeletal muscle, in one experimental model of peripheral nerve repair, at two recovery times. The rat sciatic nerve was cut at mid-thigh level and a silicone cuff containing either saline (control), LIF, or LIF plus fibronectin (L+F) was used to bridge the proximal and distal nerve stumps leaving a 1 cm gap between them. Rats were then explored at 6 or 12 weeks following the initial surgery. Regenerating nerves were assessed by measuring the diameter of myelinated axons, conduction velocity, and number of myelinated fibers. Muscle reinnervation was assessed by measuring muscle mass, force of contraction, and histologically for changes in muscle fiber type (type I and type II). In this report we demonstrate that at 6 weeks there were significant increases in 1) nerve conduction velocity, 2) myelinated axon diameter, and 3) number of myelinated axons over that of control (saline-treated) animals. Both LIF groups demonstrated a shift in type II muscle fiber area compared to saline-treated controls, with the L+F group having a significant increase in muscle mass. At 12 weeks there was an improved recovery over and above that demonstrated at 6 weeks. Muscle mass was 65% and 42% greater than control for LIF and L+F, respectively. Force of contraction, conduction velocity, myelinated fiber number, and diameter were also significantly greater for both LIF- and L+F-treated rats than saline-treated rats. These results demonstrate that LIF significantly improves the regeneration of damaged peripheral nerves and the preservation of muscle viability, resulting in greatly enhanced recovery of skeletal muscle function.

Leukemia inhibitory factor enhances the regeneration of transected rat sciatic nerve and the function of reinnervated muscle

The cytokine leukemia inhibitory factor (LIF) favors the survival and growth of axons in vitro and in vivo. Fibronectin has been shown to enhance nerve regeneration when added in combination with various growth factors including LIF. The goal of this study was to evaluate the effect of LIF plus fibronectin on the regeneration of transected nerve and functional recovery of reinnervated skeletal muscle, in one experimental model of peripheral nerve repair, at two recovery times. The rat sciatic nerve was cut at mid-thigh level and a silicone cuff containing either saline (control), LIF, or LIF plus fibronectin (L + F) was used to bridge the proximal and distal nerve stumps leaving a 1 cm gap between them. Rats were then explored at 6 or 12 weeks following the initial surgery. Regenerating nerves were assessed by measuring the diameter of myelinated axons, conduction velocity, and number of myelinated fibers. Muscle reinnervation was assessed by measuring muscle mass, force of contraction, and histologically for changes in muscle fiber type (type I and type II). In this report we demonstrate that at 6 weeks there were significant increases in 1) nerve conduction velocity, 2) myelinated axon diameter, and 3) number of myelinated axons over that of control (saline-treated) animals. Both LIF groups demonstrated a shift in type II muscle fiber area compared to saline-treated controls, with the L + F group having a significant increase in muscle mass. At 12 weeks there was an improved recovery over and above that demonstrated at 6 weeks. Muscle mass was 65% and 42% greater than control for LIF and L + F, respectively. Force of contraction, conduction velocity, myelinated fiber number, and diameter were also significantly greater for both LIF- and L + F- treated rats than saline-treated rats. These results demonstrate that LIF significantly improves the regeneration of damaged peripheral nerves and the preservation of muscle viability, resulting in greatly enhanced recovery of skeletal muscle function. J. Neurosci. Res. 47:208–215, 1997. © 1997 Wiley-Liss, Inc.

Exercise intolerance in chronic heart failure is not associated with impaired recovery of muscle function or submaximal exercise performance

This study investigated whether recovery of skeletal muscle function is impaired in patients with heart failure and whether impaired recovery is associated with abnormal submaximal systemic exercise tolerance during repeated testing. Patients with heart failure experience fatigue during daily activities. Because abnormalities of skeletal muscle play a role in their exercise intolerance, these symptoms may reflect a delay in muscle recovery and a resulting limitation in submaximal exercise tolerance. Two protocols were used. In protocol 1, knee extensor strength and endurance, and their recovery after fatiguing exercise, were evaluated in 11 patients (mean [+/- SEM] age 62 +/- 5 years, New York Heart Association functional class 2.3 +/- 0.2, ejection fraction 24 +/- 5%) and in 10 age-matched sedentary control subjects. Protocol 2 examined the recovery of knee extensor endurance and submaximal exercise tolerance, as quantified on a self-powered treadmill, over 24 h in 18 patients (mean age 65 +/- 3 years, functional class 2.4 +/- 0.2, ejection fraction 23 +/- 3%) and in 10 control subjects. Peak oxygen consumption was reduced in both heart failure groups (15.4 +/- 1.4 and 15.6 +/- 1.0 ml/kg per min) compared with that in the respective control groups (23.1 +/- 2.9 and 25.6 +/- 1.0 ml/kg per min, both p < 0.05), as was muscle endurance but not muscle strength. In protocol 1, knee extensor endurance recovered more slowly in the patients than in control subjects (to 62 +/- 4% and 87 +/- 7% of the baseline value after 5 min, respectively, p < 0.05). In protocol 2, submaximal exercise tolerance was lower in the patients with heart failure than in control subjects (1,075 +/- 116 vs. 1,390 +/- 110 m), but knee extensor endurance and walking distance recovered fully by 10 and 30 min, respectively. Although these findings confirm earlier studies that demonstrated impaired muscle endurance in patients with heart failure, the results provide no evidence that recovery of either muscle function or submaximal exercise tolerance is delayed beyond the initial 5 to 10 min after exercise.

The Effect of Hypofibrinogenemia and Fibrinolysis on Skeletal Muscle Function after Ischemia and Reperfusion

Isometric contraction to direct supramaximal tetanic stimulation of the anterior tibialis (AT) muscle was measured in 50 New Zealand White rabbits after ischemia and reperfusion. Ischemia was produced unilaterally by collateral ligation and temporary inflow control until AT muscle function decreased to <5% of contralateral (control) AT muscle and the ischemic interval was recorded. Reperfusion was carried out in one of the following ways: group I ( n = 20), release of vascular clamps (blood reperfusion [BR]); group II ( n = 10), release of vascular clamps and simultaneous intraarterial administration of 50,000 units of urokinase (urokinase reperfusion [UR]); group III ( n = 10), release of vascular clamps and simultaneous administration of 50,000 units of urokinase and 28 mg (5 units) of purified rabbit plasminogen (urokinase plasminogen reperfusion [UPR]); and group IV ( n = 10), animals defibrinated to <50 mg/dl with ancrod prior to ischemia and received BR (ancrod blood reperfusion [ABR]). During reperfusion, function was recorded every 60 min for 2 hr. Recovery of experimental muscle function is expressed as the percentage of contralateral control limb function. The mean ischemic interval (means ± SEM), to achieve <5% of contralateral control limb function, was 206.7 ± 9.9, 209.5 ± 16.6, 221.7 ± 12.5, and 272.0 ± 14.2 min for animals in groups I-IV, respectively. The mean experimental muscle function (means ± SEM) following the ischemic interval was 3.2 ± 0.8, 4.5 ± 1.4, 4.4 ± 1.2, and 3.3 ± 1.0 for groups I-IV, respectively. The difference in the ischemia time to reach <5% of control function in between the control (group I) rabbits and the animals which received ancrod (group IV) is statistically significant ( P < 0.01). After 2 hr of reperfusion, the mean muscle function was 25.5 ± 6.4 for controls (BR), 60.4 ± 18.6 for group II (UR), 72.7 ± 10.3 for group III (UPR), and 42.4 ± 9.7 for group IV (ABR). Both groups II (UR) and IlI (UPR) are statistically significant when compared to the unmodified blood reperfusion group ( P < 0.05 and P < 0.01, respectively). We conclude that urokinase infusion during reperfusion improves the recovery of skeletal muscle function after ischemia. This effect is further enhanced by the addition of substrate (plasminogen), suggesting that fibrinolysis is responsible for this effect. Defibrination with ancrod increased the tolerance of skeletal muscle to ischemia but did not significantly improve its function compared to that of unmodified blood. These experiments suggest that manipulations of the fibrinogen/fibrin system may play an important role in the tolerance of skeletal muscle to ischemia and recovery of contractile function following reperfusion.

Differential recovery of skeletal muscle and peripheral nerve function after ischemia and reperfusion

Recovery of skeletal muscle function is of prime importance in revascularization of acutely ischemic extremities. In order to study the effect of ischemia and reperfusion on peripheral nerve and skeletal muscle function, temporary unilateral hindlimb ischemia (1 or 3 hr) was induced in 12 rabbits by temporary arterial occlusion of common iliac and femoral arteries and collateral ligation. The control limb was similarly prepared without interruption of blood flow. Both anterior tibialis muscles were attached to force transducers, and the twitch and tetanic tensions were measured at the end of the ischemic interval and during reperfusion (2 hr) by either direct muscle stimulation or stimulation of the deep peroneal nerve. The ischemic limb was reperfused by removal of arterial clamps and reperfusion documented by Doppler flow over the vascular pedicle. The recovery of muscle function of the ischemic/reperfused limb relative to that of the contralateral control limb was used as the index of recovery. By the end of the ischemic interval, no contractile activity was elicited with nerve stimulation for either the 1- or the 3-hr group. After 2 hr of reperfusion, the 1-hr group regained 0.558 ± 0.116 (mean ± SEM) of control function with nerve stimulation, while the 3-hr group regained only 0.016 ± 0.005 of control function ( P < 0.01). In contrast, with direct muscle stimulation, the 1-hr group produced 0.580 ± 0.015 compared to 0.286 ± 0.042 ( P < 0.001) after 3 hr of ischemia. After 2 hr of reperfusion, the 1-hr group recovered 0.805 ± 0.059 of muscle function which was significantly better than 0.580 ± 0.077 ( P < 0.05) for the 3-hr ischemia group. Therefore, peripheral nerve is more susceptible to ischemia and short reperfusion intervals than skeletal muscle. Strategies for revascularization that may prove beneficial in the treatment of acute severely ischemic limbs may need to take into account the demonstrated injury of peripheral nerve function following relatively short periods of ischemia.