Abstract
Activin negatively affects muscle fibers and progenitor cells in aging (sarcopenia) and in chronic diseases characterized by severe muscle wasting (cachexia). High circulating activin levels predict poor survival in cancer patients. However, the relative impact of activin in mediating muscle atrophy and hampered homeostasis is still unknown. To directly assess the involvement of activin, and its physiological inhibitor follistatin, in cancer-induced muscle atrophy, we cultured C2C12 myotubes in the absence or in the presence of a mechanical stretching stimulus and in the absence or presence of C26 tumor-derived factors (CM), so as to mimic the mechanical stimulation of exercise and cancer cachexia, respectively. We found that CM induces activin release by myotubes, further exacerbating the negative effects of tumor-derived factors. In addition, mechanical stimulation is sufficient to counteract the adverse tumor-induced effects on muscle cells, in association with an increased follistatin/activin ratio in the cell culture medium, indicating that myotubes actively release follistatin upon stretching. Recombinant follistatin counteracts tumor effects on myotubes exclusively by rescuing fusion index, suggesting that it is only partially responsible for the stretch-mediated rescue. Therefore, besides activin, other tumor-derived factors may play a significant role in mediating muscle atrophy. In addition to increasing follistatin secretion mechanical stimulation induces additional beneficial responses in myotubes. We propose that in animal models of cancer cachexia and in cancer patients purely mechanical stimuli play an important role in mediating the rescue of the muscle homeostasis reported upon exercise.
Highlights
Cancer cachexia is multifactorial and characterized by tumorand host-derived factors leading to muscle wasting (Fearon et al, 2012)
The morphometric analysis focused on myotube diameter (DIA), as a marker of fiber size, on fusion index (FI), as a marker of the extent of myogenic differentiation, and on the number of nuclei per myotube (NpM), as an indication of myotube growth because of the addition of nuclei deriving from the myoblasts
Given the significance of the negative interaction between conditioned medium (CM) and DC we could perform post hoc tests, which showed that the Fusion index (FI) in the presence of CM is lower compared to all the other treatments, and that the DC does not promote fusion per se (Figure 1Bb); CM had a negative effect on the number of NpM, with no interaction with the DC, while the latter did not significantly affect the number of NpM (Figure 1Bc)
Summary
Cancer cachexia is multifactorial and characterized by tumorand host-derived factors leading to muscle wasting (Fearon et al, 2012). TGF-β family members, including activin and myostatin, are key regulators of muscle development and homeostasis (Chen et al, 2016) and have been reported to mediate cachexia (Costelli et al, 2008; Chen et al, 2014). Since they bind to activin type IIB receptor (ActRIIB), the latter has been targeted to counteract muscle wasting (Barreto et al, 2016; Hatakeyama et al, 2016; Toledo et al, 2016) or to promote muscle hypertrophy (Morvan et al, 2017) and the regenerative capacity of muscle (Formicola et al, 2018). Several organs such as the gonads (Tilbrook et al, 1996) and skeletal muscle (Ciaraldi et al, 2016) are sources of follistatin
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