Heat shock protein 70 overexpression attenuates botulinum neurotoxin type A induced skeletal muscle atrophy in rats

Abstract

Heat shock protein 70 (Hsp70) is a ubiquitous, cytoprotective protein that is up‐regulated in response to cellular stress. Botulinum neurotoxin type A (BoNT/A) administration causes a chemical denervation which leads to skeletal muscle atrophy in rats. Previous work in skeletal muscle has shown that Hsp70 inhibits both NF‐κB and FOXO activation in response to certain stimuli. During periods of atrophy, Hsp70 levels are decreased, while NF‐κB and FOXO activity are increased and required for atrophy in some models. Therefore, the purpose of the current study was to determine if electrotransfer of Hsp70 into the soleus muscle of rats, prior to BoNT/A administration, is sufficient to inhibit atrophy and NF‐κB/FOXO activation. BoNT/A administration induced ~70% atrophy of the soleus. BoNT/A + Hsp70 administration elicited only ~50% atrophy. Hsp70 prevented the BoNT/A‐induced increase in total ubiquitin conjugated proteins. Furthermore, BoNT/A‐induced NF‐κB transactivation was abolished by Hsp70 and levels of FOXO3a‐phosphorylation were maintained. In conclusion, while Hsp70 decreases total ubiquitin conjugated proteins and attenuates a portion of the observed skeletal muscle atrophy, these data suggest that pathways other than NF‐κB/FOXO may predominate in control of protein degradation. Supported by Ipsen Pharmaceuticals.