Cancer-cachexia results in severe muscle tissue wasting affecting patients quality of life and survival. Recent studies showed that physical activity increases survival in cancer patient and animal models. The underlying mechanisms, however, are still largely unknown. To identify signaling pathways involved in exercise-dependent maintenance of muscle mass and function in cachexia, we are investigating the role of serum response factor (Srf), a transcription factor of the MADS-box family, having a major role in muscular growth, differentiation and regeneration. We hypothesized that the expression and/or transcriptional activity of SRF decreases in C26 tumor bearing mice (which develop cachexia), and that exercise can rescue the compromised muscle homeostasis. Indeed, we showed a decrease of SRF expression at both RNA and protein levels in cachexia. Consistently, we showed a decrease in the expression of SRF target genes such as MyoD and SK-Actin, which suggests a decrease of SRF transcriptional activity. These tumor effects were counteracted by wheel running. Since we observed opposite effects of tumor and exercise on MyoD and Pax7 we hypothesized the involvement of a myogenic program in stem cell recruitment to muscle fibers upon exercise: indeed, we observed the recruitment of nuclei within the muscle fibers in response to exercise, which could contribute to muscle homeostasis. Based on the all above, we intend to investigate on SRF expression in greater detail and, more importantly, to formally demonstrate the role of Srf in mediating exercise effects. To do so we will analyze the extent of muscle wasting in four experimental groups: control, tumor-bearing mice, in the absence or presence of exercise training; the study will include loss of function experiments, exploiting Srf KO mice.
In cancer patients, cachexia is observed in 50-80% of advanced-stage malignancies and leads to 20% of all cancer-related deaths ( Aoyagi, 2015). Conversely, the physical activity increases the patient survival rate (Donohoe, 2011 ). Because it is not always possible to prescribe physical activity to cachectic patients due to their state, it is important to understand the molecular mechanism underlying the benefic effect of physical activity.
The idea that muscle cells possess an important, exercise-dependent secretory activity is recent and provocative. Nonetheless, more and more studies point now to exercise, especially endurance exercise, as a way to induce pleiotropic effects, spanning from an ameliorated muscle function and from an improved cardiovascular performance to an increased and healthier life span.
This study will allow a possible pharmacological treatment to mimic the effects of exercise. Our study will help to understand if the mechanical stimulation (muscle contraction) is the main responsible for the benefic effects observed with exercise or if the endocrine modifications (levels of circulating factors) induced by exercise are more important.
Our preliminary results on tumor-bearing mice showed a decrease of SRF expression at both RNA and protein levels in cachexia. Consistently, we showed a decrease in the expression of SRF target genes such as MyoD and sk-Actin which suggest a decrease of SRF transcriptional activity.
This approach would allow to validate the studies and identify a specific transcription factor induced by exercise (SRF). Taken together, it could help to find genetic program activated by physical activity.
7-Aoyagi; World J Gastrointest Oncol. 2015 Apr 15;7(4):17-29. doi: 10.4251/wjgo.v7.i4.17.
8-Donohoe; Gastroenterol Res Pract. 2011;2011:601434. doi: 10.1155/2011/601434. Epub 2011 Jun 13.