ALDH3A1-mediated Detoxification of Reactive Aldehydes Contributes to Distinct Muscle Responses to Denervation and Amyotrophic Lateral Sclerosis Progression

Different muscles exhibit varied susceptibility to degeneration in Amyotrophic Lateral Sclerosis (ALS), a fatal neuromuscular disorder. Extraocular muscles (EOMs) are particularly resistant to ALS progression and exploring the underlying molecular nature may deliver great therapeutic value. Reactive aldehyde 4-hydroxynonenal (HNE) is implicated in ALS pathogenesis and ALDH3A1 is an inactivation-resistant intracellular detoxifier of 4-HNE protecting eyes against UV-induced oxidative stress. Here we detected prominently higher levels of in mouse EOMs than other muscles under normal physiological conditions. In an ALS mouse model (hSOD1) reaching end-stage, expression was sustained at high level in EOMs, whereas substantial upregulation of occurred in soleus and diaphragm. The upregulation was less pronounced in extensor digitorum longus (EDL) muscle, which endured the most severe pathological remodeling as demonstrated by unparalleled upregulation of a denervation marker expression. Interestingly, sciatic nerve transection in wildtype mice induced and expression in an inverse manner over muscle type and time. Adeno-associated virus enforced overexpression of protected myotubes from 4-HNE-induced DNA fragmentation, plasma membrane leakage and restored MG53-mediated membrane repair. Our data indicate that may contribute to distinct muscle resistance to ALS through detoxifying reactive aldehydes.