Perturbed BMP signaling and denervation promote muscle wasting in cancer cachexia

Neuromuscular junction remodeling and deterioration due to impaired BMP signaling are associated with cancer-induced muscle wasting. Reducing waste Cancer is often associated with the development of cachexia, a severe muscle wasting process for which there are no specific therapies. The precise mechanisms and the molecular players involved in cancer-associated muscle wasting remain to be identified. Here, Sartori et al. showed that bone morphogenetic protein (BMP) was reduced in patients and rodent models. This reduction caused neuromuscular junction impairments and subsequent denervation that caused muscle mass reduction. Restoring BMP signaling preserved muscles and increased survival in tumor-bearing mice, suggesting that restoring muscle mass by targeting BMP could be effective for improving life quality and life span in patients with cancer. Most patients with advanced solid cancers exhibit features of cachexia, a debilitating syndrome characterized by progressive loss of skeletal muscle mass and strength. Because the underlying mechanisms of this multifactorial syndrome are incompletely defined, effective therapeutics have yet to be developed. Here, we show that diminished bone morphogenetic protein (BMP) signaling is observed early in the onset of skeletal muscle wasting associated with cancer cachexia in mouse models and in patients with cancer. Cancer-mediated factors including Activin A and IL-6 trigger the expression of the BMP inhibitor Noggin in muscle, which blocks the actions of BMPs on muscle fibers and motor nerves, subsequently causing disruption of the neuromuscular junction (NMJ), denervation, and muscle wasting. Increasing BMP signaling in the muscles of tumor-bearing mice by gene delivery or pharmacological means can prevent muscle wasting and preserve measures of NMJ function. The data identify perturbed BMP signaling and denervation of muscle fibers as important pathogenic mechanisms of muscle wasting associated with tumor growth. Collectively, these findings present interventions that promote BMP-mediated signaling as an attractive strategy to counteract the loss of functional musculature in patients with cancer.