Aerobic Exercise and Pharmacological Treatments Counteract Cachexia by Modulating Autophagy in Colon Cancer

Recent studies have correlated physical activity with a better prognosis in cachectic patients, although the underlying mechanisms are not yet understood. In order to identify the pathways involved in the physical activity-mediated rescue of skeletal muscle mass and function, we investigated the effects of voluntary exercise on cachexia in colon carcinoma (C26)-bearing mice. Voluntary exercise prevented loss of muscle mass and function, ultimately increasing survival of C26-bearing mice. We found that the autophagic flux is overloaded in skeletal muscle of both colon carcinoma murine models and patients, but not in running C26-bearing mice, thus suggesting that exercise may release the autophagic flux and ultimately rescue muscle homeostasis. Treatment of C26-bearing mice with either AICAR or rapamycin, two drugs that trigger the autophagic flux, also rescued muscle mass and prevented atrogene induction. Similar effects were reproduced on myotubes in vitro, which displayed atrophy following exposure to C26-conditioned medium, a phenomenon that was rescued by AICAR or rapamycin treatment and relies on autophagosome-lysosome fusion (inhibited by chloroquine). Since AICAR, rapamycin and exercise equally affect the autophagic system and counteract cachexia, we believe autophagy-triggering drugs may be exploited to treat cachexia in conditions in which exercise cannot be prescribed

Molecular, cellular and physiological characterization of the cancer cachexia-inducing C26 colon carcinoma in mouse

BACKGROUND: The majority of cancer patients experience dramatic weight loss, due to cachexia and consisting of skeletal muscle and fat tissue wasting. Cachexia is a negative prognostic factor, interferes with therapy and worsens the patients' quality of life by affecting muscle function. Mice bearing ectopically-implanted C26 colon carcinoma are widely used as an experimental model of cancer cachexia. As part of the search for novel clinical and basic research applications for this experimental model, we characterized novel cellular and molecular features of C26-bearing mice. METHODS: A fragment of C26 tumor was subcutaneously grafted in isogenic BALB/c mice. The mass growth and proliferation rate of the tumor were analyzed. Histological and cytofluorometric analyses were used to assess cell death, ploidy and differentiation of the tumor cells. The main features of skeletal muscle atrophy, which were highlighted by immunohistochemical and electron microscopy analyses, correlated with biochemical alterations. Muscle force and resistance to fatigue were measured and analyzed as major functional deficits of the cachectic musculature. RESULTS: We found that the C26 tumor, ectopically implanted in mice, is an undifferentiated carcinoma, which should be referred to as such and not as adenocarcinoma, a common misconception. The C26 tumor displays aneuploidy and histological features typical of transformed cells, incorporates BrdU and induces severe weight loss in the host, which is largely caused by muscle wasting. The latter appears to be due to proteasome-mediated protein degradation, which disrupts the sarcomeric structure and muscle fiber-extracellular matrix interactions. A pivotal functional deficit of cachectic muscle consists in increased fatigability, while the reported loss of tetanic force is not statistically significant following normalization for decreased muscle fiber size. CONCLUSIONS: We conclude, on the basis of the definition of cachexia, that ectopically-implanted C26 carcinoma represents a well standardized experimental model for research on cancer cachexia. We wish to point out that scientists using the C26 model to study cancer and those using the same model to study cachexia may be unaware of each other's works because they use different keywords; we present strategies to eliminate this gap and discuss the benefits of such an exchange of knowledge

Exercise Counteracts Cachexia And Extends Life Span In Tumor-Bearing Mice

Barcelona, Spai

Mechanisms underlying exercise-mediated rescue of cachexia

Recent studies showed that physical activity after cancer diagnosis ameliorates the prognosis, although the underling mechanisms are stili poorly understood. Cachexia, experienced by most cancer patients, is a negative prognostic factor, interfering with therapy and worsening quality of life. With the aim to delineate the pathways involved in exercise-mediated rescue of cachexia, we investigated the effects of spontaneous physical activity (wheel running) in colon carcinoma (C26)-bearing mice. All major diagnostic criteria for cachexia are reversed by exercise, including rescue of body weight, muscle atrophy and fatigue, ultimately leading to increased survival. In order to assess whether muscle contraction plays a role in the exercise-mediated rescue of cachexia, we denervated one limb of (C26)-bearing mice and assessed muscle mass following spontaneous wheel running. Interestingly, exercise exerts positive effects on (C26)-bearing mice muscle mass independently from denervation, suggesting cross-education induced by exercise on the denervated muscle. At the molecular level, exercise promotes protein synthesis, by mTOR activation, and attenuates protein degradation, by downregulating Atrogin1, in muscle from C26-bearing mice. Despite muscle damage in cachexia, satellite cells fail to fuse into muscle fibers, due to defective down-regulation of Pax7 expression. We showed that exercise rescues proper Pax7 expression levels in cachexia, which in turn may release the block of satellite celi differentiation. We propose that exercise counteracts muscle wasting through a systemic effect, by both inhibiting catabolic pathways and favouring satellite celi recruitment into muscle fibers, unveiling a novel mechanism of exercise-mediated beneficiai effects on cachexia

Muscle extracellular matrix scaffold is a multipotent environment

The multipotency of scaffolds is a new concept. Skeletal muscle acellular scaffolds (MAS) implanted at the interface of Tibialis Anterior/tibial bone and masseter muscle/mandible bone in a murine model were colonized by muscle cells near the host muscle and by bone-cartilaginous tissues near the host bone, thus highlighting the importance of the environment in directing cell homing and differentiation. These results unveil the multipotency of MAS and point to the potential of this new technique as a valuable tool in musculo-skeletal tissue regeneration

Can modification of cell physiology and growth characteristics by static magnetic field have therapeutic applications?

There is continuing progress in studies of the effect of static magnetic field (SMF) on cell growth in vivo and in vitro. The evidence in the literature including our studies indicates that SMF exerts significant effects on some physiological functions of the cell and affects their growth pattern and morphometry. This prompts us to question as to whether these effects can have therapeutic use. In the present study we demonstrate that SMF is able to modulate cell growth and differentiation in myogenic cultured cells as demonstrated by increased accumulation of actin and myosin and formation of large multinucleated myotubes. SMF is also able to spatially orient skeletal muscle cells growing on cysteamine-coated gold. Such SMF effects may have significant practical applications in tissue engineering, in particular for culturing skeletal muscle cells on conductive surfaces that is required to develop electronic device-muscle junctions for experimental and medical applications. Furthermore, SMF-enhanced parallel orientation of myotubes is relevant to tissue engineering of a highly organized tissue such as skeletal muscle. In the present study we also show that SMF produces functional changes as well. Specifically, we observe that constitutive- and exogenous oxidant- induced phosphorylation of histone H2AX and activation of ATM-S1981, the reporters of DNA damage response in human leukemic TK6 cells, are attenuated by SMF. Also, in glioblastoma cells SMF is able to modulate radiation induced DNA damage as demonstrated by comet assay. If this protective effect of SMF on DNA damage is confirmed and there is absence of potential side effects, one may consider the use of SMF for treatment of degenerative diseases such as neurodegeneration and muscle wasting thereby introducing a new therapeutic modality in regenerative and inflammation medicine

Molecular, cellular and physiological characterization of the cancer cachexia-inducing C26 colon carcinoma in mouse

Abstract Background The majority of cancer patients experience dramatic weight loss, due to cachexia and consisting of skeletal muscle and fat tissue wasting. Cachexia is a negative prognostic factor, interferes with therapy and worsens the patients' quality of life by affecting muscle function. Mice bearing ectopically-implanted C26 colon carcinoma are widely used as an experimental model of cancer cachexia. As part of the search for novel clinical and basic research applications for this experimental model, we characterized novel cellular and molecular features of C26-bearing mice. Methods A fragment of C26 tumor was subcutaneously grafted in isogenic BALB/c mice. The mass growth and proliferation rate of the tumor were analyzed. Histological and cytofluorometric analyses were used to assess cell death, ploidy and differentiation of the tumor cells. The main features of skeletal muscle atrophy, which were highlighted by immunohistochemical and electron microscopy analyses, correlated with biochemical alterations. Muscle force and resistance to fatigue were measured and analyzed as major functional deficits of the cachectic musculature. Results We found that the C26 tumor, ectopically implanted in mice, is an undifferentiated carcinoma, which should be referred to as such and not as adenocarcinoma, a common misconception. The C26 tumor displays aneuploidy and histological features typical of transformed cells, incorporates BrdU and induces severe weight loss in the host, which is largely caused by muscle wasting. The latter appears to be due to proteasome-mediated protein degradation, which disrupts the sarcomeric structure and muscle fiber-extracellular matrix interactions. A pivotal functional deficit of cachectic muscle consists in increased fatigability, while the reported loss of tetanic force is not statistically significant following normalization for decreased muscle fiber size. Conclusions We conclude, on the basis of the definition of cachexia, that ectopically-implanted C26 carcinoma represents a well standardized experimental model for research on cancer cachexia. We wish to point out that scientists using the C26 model to study cancer and those using the same model to study cachexia may be unaware of each other's works because they use different keywords; we present strategies to eliminate this gap and discuss the benefits of such an exchange of knowledge.</p