Oral Virtual Presentation (Virtual only) ESA-SRB-ANZBMS 2021

Perturbed BMP signalling and denervation promote muscle wasting in cancer cachexia (#176)

Roberta Sartori 1 2 3 , Adam Hagg 1 4 5 , Sandra Zampieri 4 6 7 , Andrea Armani 4 5 , Catherine E Winbanks 1 , Laís R Viana 2 8 , Mouna Haidar 9 , Kevin I Watt 1 2 , Hongwei Qian 1 2 , Camilla Pezzini 4 5 , Pardis Zanganeh 9 , Bradley J Turner 9 , Anna Larsson 10 , Gianpietro Zanchettin 6 , Elisa S Pierobon 6 , Lucia Moletta 6 , Michele Valmosoni 6 , Alberto Ponzoni 11 , Shady Attar 12 , Gianfranco Da Dalt 6 , Cosimo Sperti 6 , Monika Kustermann 13 , Rachel E Thomson 14 , Lars Larsson 14 15 16 , Kate L Loveland 17 18 , Paola Costelli 19 , Aram Megighian 4 , Stefano Merigliano 6 , Fabio Penna 19 , Paul Gregorevic 1 2 20 21 , Marco Sandri 4 5 7 22
  1. Baker Heart and Diabetes Institute, Melbourne, Australia
  2. Centre for Muscle Research, Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia
  3. Biomedicine Discovery Institute, Department of Physiology, Monash University, Melbourne, Victoria, Australia
  4. Department of Biomedical Sciences, University of Padova, Padova, Italy
  5. Veneto Institute of Molecular Medicine , Padova, Italy
  6. Department of Surgery, Oncology and Gastroenterology, 3rd Surgical Clinic, University of Padova, Padua, Italy
  7. Myology Center, University of Padova, Padua, Italy
  8. Department of Structural and Functional Biology, Biology Institute, University of Campinas, Sao Paulo, Brazil
  9. The Florey Institute of Neuroscience and Mental Health, Parkville, Australia
  10. Theme Cancer, Karolinska University Hospital, Solna, Sweden
  11. Department of Radiology, Padova General Hospital, Padova, Italy
  12. Department of Medicine, University Hospital of Padova, Padova, Italy
  13. Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
  14. Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
  15. Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
  16. Department of Biobehavioral Health, Pennsylvania State University, University Park, Pennsylvania, USA
  17. Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, VIC, Australia
  18. Department of Molecular and Translational Sciences, and Anatomy and Developmental Biology, Monash University, Victoria, Australia
  19. Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
  20. Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia
  21. Department of Neurology, University of Washington School of Medicine, Seattle, USA
  22. Department of Medicine, McGill University, Montreal, Quebec, Canada

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.