SRF role as a mechano-transductor in response to exercise in cancer cachexia

Introduction: Recent studies showed that physical activity increased survival in cancer patient and animal models of cancer cachexia. The underlying mechanisms, however, are still largely unknown. Methods: To identify signalling pathways involved in exercise-dependent maintenance of muscle mass and function in cachexia, we investigated the role of serum response factor (SRF)—a transcription factor playing a pivotal a role in muscular growth, differentiation and regeneration—in C26-bearing mice in the absence or presence of voluntary exercise (wheel running). Results: SRF levels are decreased at protein level in cachexia. Consistently, a decrease in the expression of SRF target genes such as MyoD and SK-actin occurs in C26-bearing mice, suggesting a decrease of SRF transcriptional activity. These tumour effects were counteracted by wheel running and associated to the rescue of muscle mass and function. However, a minimum amount of exercise (2 km/day) is necessary to keep SRF levels elevated in cachexia over a threshold which is necessary to exert beneficial effects. SRF levels inversely correlate with wasting in mice, suggesting that SRF play a role in maintaining body mass (mostly accounted for by muscle mass). We also observe the recruitment of nuclei within the muscle fibres in response to exercise, which could contribute to muscle homeostasis and is consistent with the previously observed opposite effects of tumour and exercise on MyoD and Pax7 expression. Conclusions: Our results suggest that physical activity rescues SRF expression as well as its transcriptional activity, highlighting the importance of genetic activation induced by skeletal muscle activity for muscle rescue and homeostasis. These effects could be extended to the fibre microenvironment, including myogenic stem cell activity.