Abstract
An idiopathic myopathy characterized by central nuclei in muscle fibers, a hallmark of muscle regeneration, has been observed in cancer patients. In cancer cachexia skeletal muscle is incapable of regeneration, consequently, this observation remains unaccounted for. In C26-tumor bearing, cachectic mice, we observed muscle fibers with central nuclei in the absence of molecular markers of bona fide regeneration. These clustered, non-peripheral nuclei were present in NCAM-expressing muscle fibers. Since NCAM expression is upregulated in denervated myofibers, we searched for additional makers of denervation, 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 suffering from gastrointestinal cancer, where a progressive increase in the number of central myonuclei was observed in weight stable and in cachectic patients, compared to healthy subjects. Based on all of the above, the presence of central myonuclei in cancer patients and animal models of cachexia is consistent with motor neuron loss or NMJ perturbation and could underlie a previously neglected phenomenon of denervation, rather than representing myofiber damage and regeneration in cachexia. Similarly to aging, denervation-dependent myofiber atrophy could contribute to muscle wasting in cancer cachexia.
Highlights
Skeletal muscle fibers are syncytial in nature, containing hundreds of myonuclei positioned at the periphery of each myofiber in a non-random position, which minimizes transport distances between the nuclei themselves and the other regions of the myofiber [1,2]
Since central nuclei are expected following muscle damage, we investigated the correlation between altered nuclear position and the expression of molecular markers of muscle regeneration
This finding indicates that the expression of pre- or peri-natal Myosin Heavy Chain (MHC) isoforms can be detected in all regenerating fibers at early stages of regeneration (3–6 days) and lasts at least 9 days after damage; incidentally, we noted that central nuclei are a more persistent feature of regenerating fibers as compared to MHC
Summary
Skeletal muscle fibers are syncytial in nature, containing hundreds of myonuclei positioned at the periphery of each myofiber in a non-random position, which minimizes transport distances between the nuclei themselves and the other regions of the myofiber [1,2]. Muscle fiber hypertrophy is accompanied by the addition of nuclei from stem cells, while the possible loss of nuclei following atrophy is still controversial [3]. In his seminal work, Spiro noted mispositioned myonuclei in a patient with myotubular myopathy, one of the central nuclear myopathies (CNM) [4]. The newly incorporated nuclei are moved to the center of the myofiber before being moved back to the cell periphery, rather than assuming this position immediately [10], suggesting that there is a biological need for these long-range nuclear movements in muscle development and repair. It has been established that microtubules and other cytoskeletal components play a major role in nuclear positioning [11], and that their perturbation leads to impaired muscle function [12]
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