Impact of cancer cachexia on respiratory muscle function and the therapeutic potential of exercise

Cancer cachexia is defined as a multi-factorial syndrome characterised by an ongoing loss of skeletal muscle mass and progressive functional impairment, estimated to affect 50-80% of patients and responsible for 20% of cancer deaths. Elevations in the morbidity and mortality rates of cachectic cancer patients has been linked to respiratory failure due to atrophy and dysfunction of the ventilatory muscles. Despite this, there is a distinct scarcity of research investigating the structural and functional condition of the respiratory musculature in cancer, with the majority of studies exclusively focusing on limb muscle. Treatment strategies are largely ineffective in mitigating the cachectic state. It is now widely accepted that an efficacious intervention will likely combine elements of pharmacology, nutrition and exercise. However, of these approaches, exercise has received comparatively little attention. Therefore, it is unlikely to be implemented optimally, whether in isolation or combination. In consideration of these limitations, the current review describes the mechanistic basis of cancer cachexia and subsequently explores the available respiratory- and exercise-focused literature within this context. The molecular basis of cachexia is thoroughly reviewed. The pivotal role of inflammatory mediators is described. Unravelling the mechanisms of exercise-induced support of muscle via antioxidant and anti-inflammatory effects in addition to promoting efficient energy metabolism via increased mitochondrial biogenesis, mitochondrial function and muscle glucose uptake provide avenues for interventional studies. Currently available pre-clinical mouse models including novel transgenic animals provide a platform for the development of multi-modal therapeutic strategies to protect respiratory muscles in people with cancer.