The p97/Nploc4 ATPase complex plays a role in muscle atrophy during cancer and amyotrophic lateral sclerosis

The p97 complex participates in the degradation of muscle proteins during atrophy upon fasting or denervation interacting with different adaptors.1 We investigated whether and how it might also be involved in muscle wasting in cancer, where loss of appetite occurs, or amyotrophic lateral sclerosis (ALS), where motoneuron death causes muscle denervation and fatal paralysis.2 The mRNA levels of p97 were induced in tibialis anterior (TA) of three distinct cancer cachectic mouse models but not in the non-cachectic 4T1 tumor. Similarly, p97 was high both in mRNA and protein in muscles from SOD1G93A mice. Electroporation of a shRNA for murine p97 into muscle reduced the fiber atrophy caused by colon adenocarcinoma C26 and ALS. When we interrogated a microarray we had previously generated for the expression of p97 adaptors, we found few of them induced in cachectic TA from C26-mice. By qPCR, we validated their inductions in TA of cachectic and ALS models and selected Nploc4 as the one most induced. Electroporation of a Crispr/Cas9 vector against Nploc4 into muscle reduced the fiber atrophy caused by C26 and ALS. Since Disulfiram (DSF) uncouples p97 from Nploc4,3 we treated atrophying myotubes with DSF, and found accumulated polyubiquitinated proteins and reduced degradation of long-lived proteins. DSF halves Nploc4 in the soluble muscle fraction and given to C26-mice limited the body and muscle weight loss, with no effect on tumor. The p97/Nploc4 complex plays a crucial role in muscle atrophy during these disorders and disrupting this complex might serve as a novel drug strategy.