Displaced myonuclei in cancer cachexia suggest altered innervation

Introduction. Central nuclei are considered a hallmark of skeletal muscle fiber regeneration and a sign of myopathy. We and others have previously observed central myonuclei in both pre-cachectic patients and animal models of cancer cachexia, in striking contrast with the reduced regenerative potential characterizing cachectic muscles. Methods. To elucidate the mechanisms underlying these divergent observations we further characterised the nature of central nuclei, and the muscle fiber involved, in both pre- and cachectic cancer patients, as well as in C26-tumor bearing mice. Muscle with different physiological properties, the Rectus abdominis and the Tibialis anterior, were analysed in search of denervation and regeneration markers. Results. We observed rare though measurable, non-peripheral myonuclei. The latter consisted of two distinct population: bona fide central nuclei and nuclei that are neither central nor subsarcolemmal, which we named «displaced» myonuclei. Displaced and central nuclei were detected in all types of muscle fibers. However, displaced myonuclei were the only ones to vary between control and cachectic muscles, suggesting a link with the pathological condition. Non-peripheral myonuclei were observed in the absence of muscle regeneration molecular markers, such as embryonic or fetal myosin expression. The analysis of longitudinal sections revealed that displaced myonuclei are clustered as it occurs upon denervation, and that the number of nuclear clusters increases in cachexia, coincident with N-CAM upregulation, another denervation marker. Additional denervation markers were upregulated in both human and murine cachectic muscles. Conclusions. We observed a novel phenomenon in cancer patients and animal models of cachexia: the presence of displaced nuclei consistent with motor neuron loss or NMJ perturbation. This phenomenon could underlay a previously neglected phenomenon of denervation rather that myofiber damage and regeneration in cachexia. Like in aging, denervation-dependent myofiber atrophy could contribute to the atrophic process leading to muscle wasting.