Impaired BMP signaling causes denervation, neuromuscular junction dysregulation, and muscle atrophy.

  • Major Finding: Impaired BMP signaling causes denervation, neuromuscular junction dysregulation, and muscle atrophy.

  • Concept: Overexpression of BMP signaling components reduces muscle wasting in murine cancer cachexia models.

  • Impact: Restoring BMP signaling could be a therapeutic option for patients with advanced cancer with cachexia.

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Cachexia is a significant cause of morbidity and mortality in patients with advanced cancer and is characterized by severe wasting of fat and skeletal muscle, resulting in significant functional impairment and poor outcomes. The mechanisms which underlie cachexia are poorly understood and there are currently no effective treatments. Recent studies have implicated the bone morphogenetic protein (BMP) signaling pathway as a positive regulator of muscle mass through its suppression of atrophy-associated ubiquitin ligases that promote proteolysis, prompting Sartori, Hagg, and colleagues to investigate the contribution of the BMP signaling pathway to muscle wasting in cachexia. BMP signaling was found to be downregulated in muscles from cachectic mice, whereas overexpression of the BMP signaling components caBMPR1A or BMP7 reduced the loss of muscle mass. Using immunolabeling of skeletal muscles, the authors showed that impaired BMP signaling disrupted the neuromuscular junction prior to the onset of muscle loss, with muscles exhibiting abnormal compound muscle action potentials and denervation. Re-expression of BMP pathway signaling proteins via adeno-associated viral vectors reversed this pathology. Upregulation of the BMP inhibitor Noggin was detected in cachectic muscles from tumor-bearing mice, boosted by cancer-induced factors such as IL6 and Activin A, and overexpression of Noggin in healthy mice resulted in muscle atrophy and denervation. Comparing non-cachectic tumor-bearing mice with a cachectic tumor-bearing mouse model showed IL6 and Noggin to be upregulated in cachectic muscles only. Similarly, muscle, nerve, and blood samples from patients with cancer cachexia revealed impaired BMP signaling, upregulation of Noggin, and remodeling of the neuromuscular junction. A drug screen previously identified the antiviral agent tilorone as a potential enhancer of BMP signaling; cachectic mice treated with tilorone showed restored BMP signaling that was associated with reduced muscle wasting and increased life span. These findings provide insight into the mechanisms underlying cancer cachexia and raise the possibility that promoting BMP signaling and preserving muscle innervation may hold promise for reducing mortality and morbidity associated with cancer cachexia.

Sartori R, Hagg A, Zampieri S, Armani A, Winbanks CE, Viana LR, et al. Perturbed BMP signaling and denervation promote muscle wasting in cancer cachexia. Sci Transl Med 2021;13:eaay9592.

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