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

**Background:** Cancer cachexia is a multifactorial syndrome characterized by ongoing loss of skeletal muscle mass and progressive functional impairment, affecting an estimated 50–80% of cancer patients and responsible for up to 20% of cancer deaths. Respiratory failure due to atrophy and dysfunction of ventilatory muscles has been linked to elevated morbidity and mortality in cachectic cancer patients. Despite this, the majority of cachexia research has focused on limb muscle, with a distinct scarcity of studies on respiratory musculature. Treatment strategies remain largely ineffective, and while multimodal approaches combining pharmacology, nutrition, and exercise are advocated, exercise has received comparatively little attention.

**Methods:** This is a narrative review that describes the mechanistic basis of cancer cachexia and explores the available respiratory- and exercise-focused literature. The authors conducted a systematic search of PubMed using a PICO-based strategy to identify studies on respiratory muscle function in cancer cachexia. Inclusion/exclusion criteria were defined, and 12 studies were identified and summarized in a table. The review also covers preclinical mouse models including subcutaneous C26 and LLC models, orthotopic models, and a novel genetically engineered KPP model of pancreatic ductal adenocarcinoma.

**Key Results:** The 12 identified studies on respiratory muscle in cachexia showed: diaphragm muscle mass reductions of 24% (type I), 22% (type IIa), and 29% (type IIb/x) fibres in C26 mice; MuRF1 and MAFbx mRNA elevated 2.8- and 2.2-fold in diaphragm; reduced specific force production; sarcomeric dysfunction with 27% reduction in myosin heavy chain protein; and selective impairment of hypoxic respiratory response. Pharmacological inhibition of NF-κB or MAPK pathways restored diaphragm mass and force in a lung cancer model. Mitochondrial dysfunction preceded cachexia development in LLC mice. Transcriptome analysis showed differential gene expression between tibialis anterior and diaphragm muscle, with diaphragm exhibiting disrupted architecture including increased extracellular space, irregular fibre shape, and necrotic fibres not seen in limb muscle. Exercise studies showed: 60% reduction in tumour incidence with voluntary wheel running; 52% tumour mass reduction with 16 days of high-intensity interval training in LLC mice; eccentric resistance exercise elevated mTORC1 signalling and reduced MuRF-1 mRNA in C26 mice; moderate intensity treadmill running protected against muscle wasting and reduced ROS in C26 mice; and a single 30-min session of electrically stimulated contractions increased GLUT4 mRNA 4.7-fold in cachectic mice.

**Clinical Implications:** The review highlights that respiratory muscle dysfunction in cancer cachexia is a distinct and clinically relevant issue, with reduced maximal inspiratory pressure correlated with dyspnoea prevalence and expiratory muscle dysfunction increasing pneumonia risk. Current clinical guidelines from ASCO found insufficient evidence for pharmacological intervention and no eligible exercise trials meeting review criteria. A Cochrane review identified only four relevant exercise studies in cachexia. The authors conclude that exercise has potential anti-inflammatory, antioxidant, and metabolic benefits that could counteract cachexia, but careful implementation is needed to avoid exacerbating the condition. The novel KPP mouse model, with progressive wasting over a median 158-day survival, may better represent human cachexia than rapid-onset subcutaneous models and could facilitate research on early mechanistic alterations and chronic exercise interventions.