Ricerc@Sapienza

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.