Toxicon : official journal of the International Society on Toxinology
-
Botulinum neurotoxin type A (BoNT/A) is used as a therapeutic tool to induce chemical denervation of spastically contracted muscles, yet the neurotoxin can also cause skeletal muscle atrophy. The underlying proteolytic mechanisms that induce this atrophy remain unclear. Our previous work has highlighted increased ubiquitin proteasome system (UPS) activity in soleus muscle of male Sprague Dawley rats following hind limb injection of BoNT/A, with the chymotrypsin-like activity of the 20s proteasome the most active. ⋯ Furthermore, BoNT/A-induced elevations in polyubiquitination remained elevated in BoNT/A + epoxomicin treated muscle, presumably due to epoxomicin's inhibition of the proteasome causing a back-up of polyubiquitinated proteins. Despite inhibition of the proteasome, epoxomicin was insufficient to significantly attenuate soleus muscle fiber atrophy 3 days following BoNT/A injection however, 10 days of daily epoxomicin injection was sufficient to spare ∼20% of muscle wasting. The mechanism of the remaining 80% of BoNT/A-induced atrophy presumably occurs via mechanisms outside of the 20s proteasome.
-
Venom toxicity assessments are often based upon non-native surrogate prey species that are not consumed in the wild by the venomous predator. This raises questions about the relevance of toxicity results on these "model" prey in addressing ecological or evolutionary questions about venom effects on native prey. We explore this issue by comparing the toxicity of venom from pygmy rattlesnakes (Sistrurus miliarius) on taxonomically-diverse sets of model (non-native) and native prey. ⋯ Second, native prey generally showed higher LD50 values than their non-native counterparts, suggesting greater resistance to venom from a predator with which they interact in nature. Our results suggest that researchers should use native prey to generate measures of venom toxicity that are ecologically and evolutionarily relevant. If this is not possible using "model" prey species that are close taxonomic relatives to natural prey may be a reasonable alternative.