Displaced Myonuclei in Cachexia Suggest the Occurrence of Altered Innervation

An idiopathic myopathy characterized by central nuclei in muscle fibers(Mazzotti, 2016), a hallmark of muscle regeneration, has been observed in cancer patients. In cancer cachexia skeletal muscle is incapable of regeneration (He, 2013), consequently, this observation remains unaccounted for. In C26‐tumor bearing, cachectic mice, we observed muscle fiberswith cen-tral nuclei in the absence of molecular markers of bona fideregeneration. These clustered, non‐peripheral nuclei were present in NCAM-expressing muscle fibers.Since NCAM expres-sion is upregulated in denervated myofiers, we searched for additional makers of denerva-tion, including AchRs, MUSK, and HDAC. This last one being also consistently upregulated in cachectic muscles, correlated with an increase of central myonuclei. This held true in the musculature of patients sufferingfrom gastrointestinal cancer, where a progressive increase in the number of central myonuclei was observed in weight stable and in cachectic patients, com-pared to healthy subjects. Based on all of the above, the presence of central myonuclei in can-cer patients and animal models of cachexia is consistent with motor neuron loss or NMJ per-turbation and could underlie a previously neglected phenomenon of denervation, rather than representing myofiberdamage and regeneration in cachexia. Motoneuron loss and gliosis typi-cally occur in association with neuromuscular regressive changes during ageing in mice, how-ever there are only two, contradictory reports on altered innervation in cachexia (Boehm, 2020; Daou, 2020). Based on all the above, we propose that, similarly to aging, denervation depend-ent myofiberatrophy contributes to muscle wasting in cancer cachexia.