Downregulation of Organ-Derived Activin A Attenuates Muscle Atrophy and Intramuscular Fat Infiltration in Cancer Cachexia Mice - PubMed
2 days ago
- #Muscle Atrophy
- #Activin A
- #Cancer Cachexia
- Cancer cachexia is a wasting syndrome characterized by significant skeletal muscle loss, with tumors releasing high levels of Activin A (ActA) that drive muscle wasting via the ubiquitin-proteasome pathway (UPP).
- Systemic blockade of ActA has inflammatory side effects, and targeting tumor-derived ActA alone often fails to reverse cachexia, prompting investigation into host (non-tumor) organ contributions.
- In Lewis lung carcinoma (LLC) cancer cachexia mice, ActA expression was notably increased in host organs, particularly the kidney (2.8-fold) and heart (2.7-fold).
- Organ-targeted ActA knockdown in the heart and kidney restored body weight (+6.1%), food intake (+8.4%), quadriceps mass (+17.2%), and grip strength (+10.7%), while reducing intramuscular fat infiltration and UPP signaling.
- ActA knockdown also improved mitochondrial fatty-acid oxidation regulators (CPT1B and CPT2), mitochondrial ultrastructure, and partially restored adipose mass.
- The study concludes that simultaneous downregulation of ActA in the kidney and heart attenuates muscle atrophy, improves muscle function, and mitigates adipose loss, identifying host-derived ActA as a key driver of cachexia.