Molecular and physiological effects of muscle wasting and its treatment by blocking myostatin and activins

Abstract

Muscle wasting, occurring e.g. in cancer, is associated with poor prognosis, and cancer treatments may even exacerbate the wasting. The prevention of muscle wasting has improved survival in preclinical cancer models, but the mechanisms are poorly understood. The purpose of this dissertation was to study the molecular and physiological effects of different wasting conditions and their treatment by myostatin/activin blocking. The effects of myostatin/activin blocking were studied in (1) doxorubicin (DOX) chemotherapy-treated mice, (2) tumour-bearing (TB) mice, and (3) fasted and inactive mice. Myostatin/activin blocking prevented muscle wasting in DOX-treated and TB mice. In TB mice, this was associated with improved survival, but not when myostatin/activin blocking was used to increase muscle mass only before cancer. Myostatin/activin blocking also restored bone density in DOX-treated mice, but did not counteract the impaired running capacity and the decreased physical activity in DOX-treated and TB mice, respectively. Muscle protein synthesis was decreased by DOX and restored by myostatin/activin blocking in skeletal muscle, but not in the heart. The transcriptomic responses to DOX and myostatin/activin blocking were also larger in skeletal muscle than in the heart. Muscle protein synthesis was also decreased in TB mice. This was associated with reduced mTORC1 signalling and decreased colocalization of mTOR with lysosomes, which were restored by myostatin/activin blocking. Myostatin/activin blocking also induced muscle protein synthesis in healthy mice independent of alterations in physical activity and food intake and increased the amount of mTOR colocalised with lysosomes. This study shows that prevention of muscle wasting by myostatin/activin blocking improves survival in experimental cancer and has other beneficial effects beyond skeletal muscle in chemotherapy and cancer. In addition, maintaining muscle mass may be more beneficial in terms of survival than having a larger muscle mass before the cachectic stimulus. Finally, muscle protein synthesis and mTORC1 signalling induced by myostatin/activin blocking may be mediated via increased mTOR-lysosome colocalisation in healthy and cachectic muscles. This dissertation contributes to the cachexia research with novel results that may advance the development of strategies to prevent or treat cachexia.