Preventing respiratory muscle dysfunction to improve survival in chronic disease by targeting a novel drug-exercise therapeutic axis

Abstract

With the increase in the life expectancy of the population it is estimated that millions of new cases of chronic diseases, such as cancer and heart failure, will be diagnosed in the coming years. Advances in the treatments have significantly improved the survival of patients; however, associated factors such as skeletal muscle mass loss and dysfunction (named cachexia) affect not only patient quality of life, but tolerability and response to treatments. Patients with cachexia exhibit shorter survival than non-cachectic patients, and one major site of cachexia is the main muscle of respiration, the diaphragm. It is known that life-threatening respiratory failure is the major cause of death in cancer patients. However, the molecular basis of diaphragm weakness are poorly understood. Our group have observed that aerobic exercise training (AET) can prevent clinical progression of cancer cachexia in mice, able to reduce tumour burden and severity in addition to modulating skeletal muscle Akt/mTORC1 signalling and muscle size. We have also found in a skeletal muscle proteomic screening a family of eukaryotic initiation factors (eIF-2 signalling) as the most downregulated in the cachectic muscles (FAPESP thematic project #2015/22814-5). eIFs are important to translation initiation and its dysfunction seems to be a feature of cachectic muscles, since we have observed that in our model of cancer cachexia (colon carcinoma CT26) and it was observed in muscle samples from patients. Dr Bowen from University of Leeds (our partner in this application) has recently developed a novel and promising muscle-specific chemical agent (ID#704946) to treat chronic disease-related muscle wasting. It was shown this compound has beneficial effect in attenuating cardiac cachexia and diaphragm dysfunction. It was also reported the compound could restore the levels of the eIF2B-´, thus suggesting its capacity of modulating translation initiation, which in addition to the activation of Akt/mTORC1 signalling, is the key processes of muscle hypertrophy. In a current postdoctoral fellowship linked to our Thematic project (FAPESP #2016/26169-0), we have tested whether muscles can maintain its growth ability post-cancer cachexia. we have demonstrated, thought the in vivo manipulation of the Akt/mTORC1 pathway, that the muscles are still able to hypertrophy despite being stressed in such severe atrophic scenario. Taking into consideration that AET can prevent cancer cachexia and after activation of Akt/mTOR signalling the muscles can grow again, and that, up to now, no pharmacological agent against muscle wasting has been identified, it is worth to address the effects of a new and muscle-specific chemical compound. The thematic FAPESP project linked to this application has focus on new therapeutic paradigms based on the cellular and molecular principles underlying treatment of cardiovascular disease and cancer with emphasis on cardiac and skeletal muscle toxicity. This FAPESP/SPRINT application will allow us to study the isolated and combined effects of AET and ID#704946 treatment as a novel approach to preserve respiratory muscle, extend survival, and delay disease progression. For doing that, we have established a multidisciplinary international collaboration combining expertise in clinical exercise physiology and molecular muscle biology. If successful, both groups will, for the first time, study the combination of AET and a muscle-specific drug as an approach to treat chronic disease wasting. Our main results will contribute to the validation of that compound as a future pharmacological interventions against chronic diseases-related cachexia. Therefore, this FAPESP/SPRINT project is a valuable opportunity to strengthen the partnership between the University of Sao Paulo and the University of Leeds, and the thematic FAPESP project serves as a platform for sharing expertise, exchange of students, and to promote research and educational activities. (AU)