Development and Preclinical Testing of a Novel Neurodenervant in the Rat: C3 Transferase Mitigates Botulinum Toxin's Adverse Effects on Muscle Mechanics.

Abstract

Spasticity, characterized by elevated muscle tone, is commonly managed with botulinum toxin type A (BTX-A). However, BTX-A can paradoxically increase passive muscle forces, narrow muscles' length range of force exertion (l_range), and elevate extracellular matrix (ECM) stiffness. C3 transferase, known to inhibit myofibroblast and fascial tissue contractility, may counteract ECM stiffening. This study investigated whether combining BTX-A with C3 transferase reduces active forces without altering passive forces or l_range. Additionally, we examined the isolated effects of C3 transferase on muscle levels. Male Wistar rats received injections into the tibialis anterior (TA): Control (n = 7, saline) and C3 + BTX-A (n = 7, 2.5 µg C3 + 0.1U BTX-A). TA forces were measured one month post-injection, and isolated C3 transferase effects were assessed in separate groups (Control and C3, n = 6 each). Active forces were 43.5% lower in the C3 + BTX-A group compared to the Control group. No differences between groups in passive forces (p = 0.33) or l_range (p = 0.19) were observed. C3 transferase alone had no significant effect on relative muscle mass (p = 0.298) or collagen content (p = 0.093). Supplementing BTX-A with C3 transferase eliminates BTX-A's adverse effects at the muscle level. C3 transferase alone causes no atrophy or collagen increase, which are key factors in BTX-A-induced ECM stiffening. This novel neurodenervant formula shows promise for advancing spasticity management.