Long-term BTX-A effects on bi-articular muscle: Higher passive force, limited length range of active force production and unchanged intermuscular interactions.

Botulinum toxin type-A (BTX-A) is commonly used for spasticity management aiming at reducing joint stiffness and increasing joint range of motion in CP patients. However, previous animal studies showed acutely increased passive forces and a narrowerlength range of active force exertion (lrange) for muscles exposed. BTX-A can spread affecting mechanics of several muscles in a compartment, but it was shown acutely to diminishepimuscular myofascial force transmission (EMFT). Yet, our understanding of these effects in the long-term is limited and they need to be tested in a bi-articular muscle. The goal was to test the following hypotheses in a long-term rat model: exposure to BTX-A (i) has no effects onlrangeand passive forces of bi-articular extensor digitorum longus (EDL) muscle and (ii) diminishes EMFT. Male Wistar rats were divided into two groups: BTX-A and control (0.1 units of BTX-A or only saline was injected into the tibialis anterior). Isometric proximal and distal EDL forces were measured simultaneously, one-month post-injection. Proximally and distally lengthening the muscle showed that BTX-A causes a significantly narrowerlrange(by 14.7% distally and 32.2% proximally) and significantly increased passive muscle forces (over 2-fold both distally and proximally). Altering muscle position at constant length showed that BTX-A does not change EMFT. The findings reject both hypotheses showing that long-term exposure to BTX-A compromises bi-articular muscle's contribution to motion for both joints and the muscle's mechanical interaction with the surroundings remains unaffected. These effects which may compromise long-term spasticity management should be studied in CP patients.

Long-Term Effects With Potential Clinical Importance of Botulinum Toxin Type-A on Mechanics of Muscles Exposed.

Botulinum toxin type-A (BTX-A) is widely used for spasticity management and mechanically aims at reducing passive resistance at the joint and widening joint range of movement. However, recent experiments on acute BTX-A effects showed that the injected rat tibialis anterior (TA) muscle's passive forces increased, and the length range of active force exertion (l range) did not change. Additionally, BTX-A was shown to spread into non-injected muscles in the compartment and affect their mechanics. Whether those effects persist in the long term is highly important, but unknown. The aim was to test the following hypotheses with experiments conducted in the anterior crural compartment of the rat: In the long term, BTX-A (1) maintains l range, (2) increases passive forces of the injected TA muscle, and (3) spreads into non-injected extensor digitorum longus (EDL) and the extensor hallucis longus (EHL) muscles, also affecting their active and passive forces. Male Wistar rats were divided into two groups: BTX-A and Control (0.1 units of BTX-A or only saline was injected into the TA). Isometric forces of the muscles were measured simultaneously 1-month post-injection. The targeted TA was lengthened, whereas the non-targeted EDL and EHL were kept at constant length. Hydroxyproline analysis was done to quantify changes in the collagen content of studied muscles. Two-way ANOVA test (for muscle forces, factors: TA length and animal group) and unpaired t or Mann-Whitney U test (for l range and collagen content, where appropriate) were used for statistical analyses (P < 0.05). BTX-A caused significant effects. TA: active forces decreased (maximally by 75.2% at short and minimally by 48.3%, at long muscle lengths), l range decreased (by 22.9%), passive forces increased (by 12.3%), and collagen content increased (approximately threefold). EDL and EHL: active forces decreased (up to 66.8%), passive force increased (minimally by 62.5%), and collagen content increased (approximately twofold). Therefore, hypothesis 1 was rejected and 2 and 3 were confirmed indicating that previously reported acute BTX-A effects persist and advance in the long term. A narrower l range and an elevated passive resistance of the targeted muscle are unintended mechanical effects, whereas spread of BTX-A into other compartmental muscles indicates the presence of uncontrolled mechanical effects.