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Effects of botulinum toxin-induced paralysis on postnatal development of the supraspinatus muscle.

ABSTRACT: The mechanical environment plays an important role in musculoskeletal tissue development. The present study characterized changes in supraspinatus muscle due to removal of mechanical cues during postnatal development. An intramuscular injection of botulinum toxin type A (BTX) was used to induce and maintain paralysis in the left shoulders of mice since birth while the right shoulders received saline and served as contralateral controls. A separate group of animals was allowed to develop normally without any injections. Muscles were examined postnatally at various time points. The maximum isometric tetanic force generated by the muscle was significantly reduced in the BTX group compared to saline and normal groups. The paralyzed muscles were smaller and showed significant muscle atrophy and fat accumulation on histologic evaluation. Myogenic genes myogenin, myoD1, myf5, myf6, and fast type II myosin heavy chain (MHC) isoform were significantly upregulated while slow type I MHC isoform was significantly downregulated in the BTX group. Adipogenic genes C/EBP?, PPAR?2, leptin, and lipoprotein lipase were significantly upregulated in the BTX group. Results indicate that reduced muscle loading secondary to BTX-induced paralysis leads to fat accumulation and muscle degeneration in the developing muscle. Understanding the molecular and compositional changes in developing supraspinatus muscles may be useful for identifying and addressing the pathological changes that occur in shoulder injuries such as neonatal brachial plexus palsy.

SUBMITTER: Das R

PROVIDER: S-EPMC3608102 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Effects of botulinum toxin-induced paralysis on postnatal development of the supraspinatus muscle.

Das Rosalina R Rich Jason J Kim H Mike HM McAlinden Audrey A Thomopoulos Stavros S

Journal of orthopaedic research : official publication of the Orthopaedic Research Society 20100827 2

The mechanical environment plays an important role in musculoskeletal tissue development. The present study characterized changes in supraspinatus muscle due to removal of mechanical cues during postnatal development. An intramuscular injection of botulinum toxin type A (BTX) was used to induce and maintain paralysis in the left shoulders of mice since birth while the right shoulders received saline and served as contralateral controls. A separate group of animals was allowed to develop normally ...[more]

PMID: 20803483

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Project description:Experimental studies have demonstrated that botulinum neurotoxin serotype A (BoNT/A) causes flaccid paralysis by a multi-step mechanism. Following its binding to specific receptors at peripheral cholinergic nerve endings, BoNT/A is internalized by receptor-mediated endocytosis. Subsequently its zinc-dependent catalytic domain translocates into the neuroplasm where it cleaves a vesicle-docking protein, SNAP-25, to block neurally evoked cholinergic neurotransmission. We tested the hypothesis that mathematical models having a minimal number of reactions and reactants can simulate published data concerning the onset of paralysis of skeletal muscles induced by BoNT/A at the isolated rat neuromuscular junction (NMJ) and in other systems. Experimental data from several laboratories were simulated with two different models that were represented by sets of coupled, first-order differential equations. In this study, the 3-step sequential model developed by Simpson (J Pharmacol Exp Ther 212:16-21,1980) was used to estimate upper limits of the times during which anti-toxins and other impermeable inhibitors of BoNT/A can exert an effect. The experimentally determined binding reaction rate was verified to be consistent with published estimates for the rate constants for BoNT/A binding to and dissociating from its receptors. Because this 3-step model was not designed to reproduce temporal changes in paralysis with different toxin concentrations, a new BoNT/A species and rate (k(S)) were added at the beginning of the reaction sequence to create a 4-step scheme. This unbound initial species is transformed at a rate determined by k(S) to a free species that is capable of binding. By systematically adjusting the values of k(S), the 4-step model simulated the rapid decline in NMJ function (k(S) >or= 0.01), the less rapid onset of paralysis in mice following i.m. injections (k (S) = 0.001), and the slow onset of the therapeutic effects of BoNT/A (k(S) < 0.001) in man. This minimal modeling approach was not only verified by simulating experimental results, it helped to quantitatively define the time available for an inhibitor to have some effect (t(inhib)) and the relation between this time and the rate of paralysis onset. The 4-step model predicted that as the rate of paralysis becomes slower, the estimated upper limits of (t(inhib)) for impermeable inhibitors become longer. More generally, this modeling approach may be useful in studying the kinetics of other toxins or viruses that invade host cells by similar mechanisms, e.g., receptor-mediated endocytosis.

Dataset Information

Effects of botulinum toxin-induced paralysis on postnatal development of the supraspinatus muscle.

Publications

Effects of botulinum toxin-induced paralysis on postnatal development of the supraspinatus muscle.

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