The mechanical stimulation of myotubes counteracts the effects of tumor-derived factors through the modulation of the activin/follistatin ratio

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

Neurohypophyseal hormones and skeletal muscle: a tale of two faces

The neurohypophyseal hormones vasopressin and oxytocin were invested, in recent years, with novel functions upon striated muscle, regulating its differentiation, trophism, and homeostasis. Recent studies highlight that these hormones not only target skeletal muscle but represent novel myokines. We discuss the possibility of exploiting the muscle hypertrophying activity of oxytocin to revert muscle atrophy, including cancer cachexia muscle wasting. Furthermore, the role of oxytocin in cardiac homeostasis and the possible role of cardiac atrophy as a concause of death in cachectic patients is discussed

Mechanisms involved in the cross-talk between humoral and mechanical cues underlying muscle wasting in cachexia

Introduction. Exercise training improves quality of life and survival of cancer patients. In an animal model of cancer cachexia we demonstrated that wheel running counteracts cachexia by releasing the autophagic flux. Exercise pleitropic effects include the alteration of circulating factors in favour of an anti-inflammatory environment and the activation of mechanotransduction pathways in muscle cells. Our goal is to assess whether mechanostransduciton per se is sufficient to elicit exercise effects in the presence of pro-cachectic factors of tumor origin. Serum response factor (SRF) is a transcription factor of pivotal importance for muscle homeostasis, which is activated with its co-factor MRTF by mechanostranduction in a way dependent on actin polymerisation. Methods. We use C26 tumor-bearing mice, in the absence or presence of wheel running, and mixed cultures of C2C12 myotubes and myoblasts treated with C26 conditioned medium (CM) in the absence or presence of cyclic stretch to mimic the mechanical stimulation occurring upon exercise. Results. In vivo both SRF expression and activity are differentially modulated by the C26 tumor, i.e. by humoral factors, and by exercise. In vitro we showed that CM had a negative effect on muscle cell cultures, both in terms of myotube atrophy and of myoblast recruitment and fusion, and that these effects were counteracted by cyclic stretch. We showed that CM repressed SRF-MRTF transcriptional activity, while mechanical stretch rescued their transcriptional activity; in addition, loss of function experiments demonstrated that SRF was necessary to mediate the beneficial effects of mechanical stimulation on muscle cells. At least part of the observed effects were mediated by the balance of pro- and anti-myogenic factor of the TGFbeta superfamily. Conclusions. We propose that the positive effects of exercise on cancer patients and mice may be specifically due to a mechanical response of muscle fibers affecting the secretion of myokines

L’ocytocine, un traitement hormonal contre la cachexie dans des modèles pré-cliniques

L'ocytocine (OT), une hormone neurohypophysaire, affecte le système nerveux central (SNC), l'utérus et les glandes mammaires. Il a été récemment démontré que l'OT favorise la différenciation myogénique et la régénération musculaire. En effet, les niveaux d'OT diminuent avec l'âge et son administration exogène contrecarre la sarcopénie chez les souris âgées. La cachexie est un syndrome caractérisé par une sévère fonte musculaire. Nous avons remarqué des niveaux inférieurs d'OT circulant chez les patients cachectiques atteints de cancer. Pour prouver que l'OT inhibe les facteurs dérivés de la tumeur, nous avons d'abord effectué des expériences in vitro montrant que l'inhibition de la différenciation myogénique exercée par le milieu conditionné par la tumeur C26 (CM) est inversée par le cotraitement avec l'OT. Ceci a été confirmée in vivo, car l'OT accélérait la régénération musculaire suite à une lésion focale, inhibé par le TNF. Dans un modèle préclinique, OT a restauré la masse musculaire squelettique, la taille des fibres et inhibé le catabolisme protéique. Nous nous sommes concentrés sur les effets de la tumeur et d’OT sur le métabolisme des protéines, en marquant spécifiquement les protéines nouvellement synthétisées. Dans les myoblastes co-cultivés avec des cellules tumorales, nous avons observé une diminution des protéines nouvellement synthétisées, contrecarré par le traitement OT. Nous montrons pour la première fois que l'OT est efficace pour contrecarrer les effets des facteurs dérivés de la tumeur.Oxytocin (OT), a neurohypophyseal hormone, affects the central nervous system (CNS), uterus, and mammary glands. OT has recently been shown to promote myogenic differentiation and muscle regeneration. Indeed, OT levels decrease with age and its exogenous administration counteracts sarcopenia in aged mice. Cachexia is a syndrome characterized by severe muscle wasting. We noticed lower levels of circulating OT in cachectic cancer patients. To prove that OT inhibits tumor-derived factors, we first performed in vitro experiments showing that the inhibition of myogenic differentiation exerted by C26 tumor-conditioned medium (CM) is reversed by co-treatment with OT. We confirmed in vivo that OT accelerated muscle regeneration following focal injury, inhibited by TNF. In a preclinical model, OT restored skeletal muscle mass, fiber size, and inhibited protein catabolism. We focused on the effects of tumor and OT on protein metabolism, specifically labeling newly synthesized proteins. In myoblasts co-cultured with tumor cells, we observed a decrease in newly synthesized proteins, counteracted by OT treatment. We show for the first time that OT is effective in counteracting the effects of tumor-derived factors

Basking in their Niche: Stem Cells with Myogenic Potential as a Target to Combat Cachexia

Skeletal muscle contains several myogenic populations: satellite cells, muscle derived stem cells, PW1+ stem cells, mesoangioblasts / pericytes, fibroadipogenic progenitor cells, and hematopoietic stem cells. In response to muscle damage in cachexia, these myogenic populations proliferate, but fail to fuse into myofibers. Substantial evidence points to pro-inflammatory cytokines and other anti-myogenic factors, which apparently are responsible for this paradoxical increase in the muscle stem-cell pool in wasting muscle. Therapeutic efforts are currently aimed at counteracting myofiber catabolism and atrophy; nonetheless, functional myogenic cells could be an additional therapeutic targets. As in dystrophic muscles, myogenic cells can sustain muscle homeostasis for a long time, even in the presence of overt muscle damage and wasting. Many tools are already available to stimulate their differentiation, from exercise to the pharmacological removal of inhibitory signals blocking this very differentiation. However, an extended characterization of the various myogenic stem-cell populations, in search of the one resistant to cachectic factors, has not been performed to date. The identification of either an engineered or an endogenous myogenic cell type able to differentiate or fuse to cachectic myofibers in the presence of a non-permissive milieu would represent a revolutionary approach to counteract cachexia

Opposite effects of tumor-derived cytokines and mechanical stimulation on muscle stem cell activity and muscle homeostasis

Cancer cachexia is a muscle wasting syndrome, characterized by muscle fiber atrophy and hampered satellite cell (SC) myogenic potential, ultimately leading to morbidity, lowered quality of life, and death. Exercise training improves quality of life and survival of cancer patients and its beneficial effects can be mimicked by wheel running in mice.1,2 In an animal model of cancer cachexia we demonstrated that wheel running counteracts cachexia by releasing the autophagic flux and by lowering Pax7 expression, which blocks SC myogenic progression.3,4. Exercise pleiotropic effects include the alteration of circulating factors in favor of an anti-inflammatory environment and the activation of mechanotransduction pathways in muscle cells. Serum response factor (SRF) is a transcription factor of pivotal importance for muscle homeostasis, which is activated with its co-factor MRTF by mechanotransduction in a way dependent on actin polymerization.5 Our goal was to assess whether mechanotransduction per se is sufficient to elicit exercise effects in the presence of pro-cachectic factors of tumor origin and to characterize the mechanotransduction signals involved

Research Regarding the Use of Benctonic Macro Invertebrates on Bega River Water Quality Determination in the Timisoara Area

The benthic macro invertebrates are considered in this century to be one of the most important biological parameters for the quality of surface waters and they have the following characteristics: they live in constant contact with the sediments where pollutants are accumulated, have a fairly long-lasting lifecycle, are present in all types of aquatic ecosystems, are easily collected and quite easy to identify. The aim of this paper is to show the use of benthic macro invertebrates on Bega River water quality determination in the Timisoara area. After the identification of macro invertebrates has done, it have been performed the density, abundance and frequency of the sample. Based on these values, we can say that the upstream segment waters falls into the category of superior quality compared to the waters of the central segment, especially in the downstream segment