Abstract

Background Cancer cachexia is a multifactorial wasting syndrome marked by profound skeletal muscle loss. Tumours can release high levels of Activin A (ActA), which activates the ubiquitin-proteasome pathway (UPP) and drives muscle wasting. Systemic blockade of the ActA pathway is associated with inflammatory adverse effects, and tumour-restricted targeting alone often fails to reverse cachexia. We asked whether ActA produced by host (nontumour) organs contributes to circulating ActA and muscle wasting. Methods We profiled ActA across tissues and in serum in Lewis lung carcinoma (LLC) cancer cachexia mice to generate an organ-wide expression map. Functional studies were then performed using adeno-associated-virus (AAV)-knockdown in the heart (cTnT/hTCF21 promoters) and kidney (CMV promoter), followed by cachexia induction. Body weight (BW), food intake, skeletal muscle mass, muscle function and muscle histomorphology were assessed. Mitochondrial ultrastructure and lipid metabolic pathways in muscle and adipose tissue were also examined. Results LLC cachexia mice exhibited significant reductions in body weight ( − 6.0%, p < 0.05), food intake (−9.9%, p < 0.05), quadriceps mass (−15.3%, p < 0.05) and grip strength (−13.0%, p < 0.0001) compared with non–tumour-bearing (NTB) mice ( n = 6–12/group). ActA expression was markedly increased in the host organs, particularly in the kidney (2.8-fold vs. NTB, p < 0.001) and heart (2.7-fold vs. NTB, p < 0.05) ( n = 10/group). Compared with the sh-NC, organ-targeted ActA knockdown restored body weight (+6.1%, p < 0.05) and food intake (+8.4% , p < 0.05), increased quadriceps mass (+17.2%, p < 0.05) and grip strength (+10.7%, p < 0.01), reduced intramuscular fat infiltration and attenuated UPP signalling ( n = 8–16/group). These effects were accompanied by increased expression of the mitochondrial fatty-acid oxidation regulator carnitine palmitoyltransferase 1B (CPT1B) (+42.3% of mRNA level; +30.9% of protein level; both p < 0.05)