Journal of Reconstructive Microsurgery 08/2006; 22(06). DOI:10.1055/s-2006-949704 · 1.01 Impact Factor
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ABSTRACT: Botulinum toxin A (BoNT-A) is a potent biological toxin widely used for the management of skeletal muscle spasticity or dynamic joint contracture. Intramuscular injection of BoNT-A causes muscle denervation, paresis, and atrophy. This clinical effect of botulinum toxin A lasts 3 to 6 months, and injected muscle eventually regains muscle mass and recovers muscle function. The goal of the present study was to characterize the molecular and cellular mechanisms leading to neuromuscular junction (NMJ) regeneration and skeletal muscle functional recovery after BoNT-A injection. Fifty-six 1-month-old Sprague-Dawley rats were used. Botulinum toxin A was injected into the left gastrocnemius muscle at a dosage of 6 units/kg body weight. An equivalent volume of saline was injected into the right gastrocnemius muscle to serve as control. The gastrocnemius muscle samples were harvested from both hind limbs at 3 days, 7 days, 15 days, 30 days, 60 days, 90 days, 180 days, and 360 days after administration of toxin. In addition, the gastrocnemius muscles from 1-month-old rats with no injections were harvested to serve as uninjected control group. Muscle samples were processed and mRNA was extracted. Real-time polymerase chain reaction (PCR) and gene microarray technology were used to identify key molecules involved in NMJ stabilization and muscle functional recovery. More than 28,000 rat genes were analyzed and approximately 9000 genes are expressed in the rat gastrocnemius muscle. Seven days following BoNT-A injection, 105 genes were upregulated and 59 genes were downregulated. Key molecules involved in neuromuscular junction (NMJ) stabilization and muscle functional recovery were identified and their time course of gene expression following BoNT-A injection were characterized. This animal study demonstrates that following intramuscular injection of BoNT-A, there is a sequence of cellular events that eventually leads to NMJ stabilization, remodeling, and myogenesis and muscle functional recovery. This recovery process is divided into two stages (aneural and neural) and that the IGF-1 signaling pathway play a central role in the process.
Journal of Orthopaedic Research 05/2006; 24(5):1128-35. DOI:10.1002/jor.20131 · 2.97 Impact Factor
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ABSTRACT: The muscle and nerve responses to stresses applied during distraction osteogenesis have not been clearly defined. This study hypothesized that distraction resulting in 30% lengthening decreases muscle force generation of the lengthened muscle and increasing the frequency of distraction attenuates the decrease of force generation accompanying lengthening. This study investigated the effects of different distraction frequencies on neuromuscular recovery in a rabbit model. Animals were assigned into group 1 (low-frequency distraction) and group 2 (high-frequency distraction). Distraction was continued until a 30% increase in the original tibial length was achieved. After consolidation of the osteotomy, knee and ankle range of motion, muscle force generation, and neuromuscular junction parameters were evaluated. Lengthening of 30% resulted in significantly decreased range of motion compared with the control leg (P < 0.05). Lengthening of 30% also substantially decreased force generation of the peroneus longus muscle. However, force generation of the peroneus longus muscle in the high-frequency group was 70.5% +/- 6.5% of the control side, significantly higher than that in the low-frequency distraction group (49.7% +/- 4.8% of the control side, P < 0.05). There was no statistical difference between the 2 groups in neuromuscular junction morphology, although an abnormal shape of the postsynaptic neuromuscular junction was observed after distraction. The use of a high-frequency distraction technique during limb lengthening may result in a reduction in impairment of knee and ankle range of motion and improved muscle function compared with that observed with the use of low-frequency distraction. Repeated microtrauma to the soft tissues associated with high-frequency distraction may facilitate the regenerative capacity of the soft tissues and result in an improved outcome of muscle and nerve function.
Journal of Pediatric Orthopaedics 01/2006; 26(5):628-33. DOI:10.1097/01.bpo.0000226283.39319.06 · 1.43 Impact Factor