Sartori et al., Sci. Transl. Med. 13, eaay9592 (2021) 4 August 2021 SCIENCE TRANSLATIONAL MEDICINE | RESEARCH ARTICLE 1 of 16 CACHEXIA Perturbed BMP signaling and denervation promote muscle wasting in cancer cachexia Roberta Sartori 1,2,3† , Adam Hagg 1,4,5† , Sandra Zampieri 3,6,7‡ , Andrea Armani 2,3‡ , Catherine E. Winbanks 1‡ , Laís R. Viana 4,8 , Mouna Haidar 9 , Kevin I. Watt 1,4 , Hongwei Qian 1,4 , Camilla Pezzini 2,3 , Pardis Zanganeh 9 , Bradley J. Turner 9 , Anna Larsson 10 , Gianpietro Zanchettin 6 , Elisa S. Pierobon 6 , Lucia Moletta 6 , Michele Valmasoni 6 , Alberto Ponzoni 11 , Shady Attar 12 , Gianfranco Da Dalt 6 , Cosimo Sperti 6 , Monika Kustermann 13 , Rachel E. Thomson 1,4 , Lars Larsson 14,15,16 , Kate L. Loveland 17,18 , Paola Costelli 19 , Aram Megighian 3 , Stefano Merigliano 6 , Fabio Penna 19 , Paul Gregorevic 1,4,20,21 * § , Marco Sandri 2,3,7,22 * § 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. INTRODUCTION Cachexia, a multifactorial syndrome characterized by severe wasting of skeletal muscle and fat despite nutritional support, is a common feature of advanced cancer (1, 2). The increasingly debilitating functional impairment of muscle experienced by cachectic individuals increases morbidity and reduces both tolerance and responsiveness to treatment regimens, complicating patient management and ultimately accounting for up to 30% of deaths associated with advanced cancer (3). Although the pathogenic mechanisms responsible for cancer cachexia remain incompletely defined, the loss of muscle mass and strength is considered the most important clinical feature of cancer cachexia and a key predictor of poor outcomes (4). Preservation of muscle mass independent of fat loss and tumor growth has been shown to extend survival in animal models of cachexia (5). These observations suggest that interventions capable of conserving and/or restoring functional muscle mass offer considerable potential in combination with anticancer regimens to enhance patient outcomes. Muscle atrophy arises when hyperactivation of proteolysis and organelle degradation exceeds rates of protein synthesis and organelle biogenesis. Proteolysis occurs via calcium-dependent proteolytic pathways (6) and ubiquitin-mediated proteasomal and autophagic lysosomal processes (7) that are potentiated when cellular signaling events promote excessive transcription of genes encoding for rate- limiting enzymes of the degradative systems (8). As a regulator of protein synthesis and degradation processes, the transforming growth factor–b (TGFb) network has emerged as one of the most important governors of muscle mass (9–11). Specific TGFb family ligands that use Activin receptors (ActRs) and SMAD2/3 second messengers modulate protein turnover in favor of catabolism and have been associated with conditions characterized by muscle atrophy, including cachexia (12–14). Inhibition of ActR-SMAD2/3 signaling has been proposed as a therapeutic for cancer cachexia, after studies reporting improved survival in mice concomitant with preservation of muscle mass despite unchanged tumor growth, fat loss, and proinflammatory cytokine production (5). However, clinical translation has been hampered by the challenges of developing interventions that achieve efficacious targeting of excessive ActR-SMAD2/3 signaling in muscle without side effects in other cell types and tissues (15, 16), 1 Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia. 2 Veneto Institute of Molecular Medicine, 35129 Padova, Italy. 3 Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy. 4 Centre for Muscle Research, Department of Anatomy and Physiology, University of Melbourne, Melbourne, VIC 3010, Australia. 5 Biomedicine Discovery Institute, Department of Physiology, Monash University, Melbourne, VIC 3800, Australia. 6 Department of Surgery, Oncology and Gastro- enterology, 3rd Surgical Clinic, University of Padova, 35128 Padua, Italy. 7 Myology Center, University of Padova, 35122 Padua, Italy. 8 Department of Structural and Functional Biology, Biology Institute, University of Campinas, Campinas, São Paulo 13083-97, Brazil. 9 The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia. 10 Theme Cancer, Karolinska University Hospital, Solna 171 76, Sweden. 11 Department of Radiology, Padova General Hospital, 35121 Padova, Italy. 12 Department of Medicine, University Hospital of Padova, 35121 Padova, Italy. 13 Center for Anatomy and Cell Biology, Medical University of Vienna, 1090 Vienna, Austria. 14 Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden. 15 Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden. 16 Department of Biobehavioral Health, The Pennsylvania State Uni- versity, University Park, PA 16802, USA. 17 Centre for Reproductive Health. Hudson Institute of Medical Research, Clayton, VIC 3168, Australia. 18 Department of Mo- lecular and Translational Sciences, and Anatomy and Developmental Biology, Monash University, VIC 3800, Australia. 19 Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, Italy. 20 Department of Biochemistry and Molecu- lar Biology, Monash University, VIC 3800, Australia. 21 Department of Neurology, University of Washington School of Medicine, Seattle, WA 98195, USA. 22 Depart- ment of Medicine, McGill University, Montreal, QC H4A 3J1, Canada. *Corresponding author. Email: pgre@unimelb.edu.au (P.G.); marco.sandri@unipd.it (M.S.) †These authors contributed equally to this work. ‡These authors contributed equally to this work. §These authors contributed equally to this work. Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. 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