title: Smad7 gene delivery prevents muscle wasting associated with cancer cachexia in mice.
abstract: Patients with advanced cancer often succumb to complications arising from striated muscle wasting associated with cachexia. Excessive activation of the type IIB activin receptor (ActRIIB) is considered an important mechanism underlying this wasting, where circulating procachectic factors bind ActRIIB and ultimately lead to the phosphorylation of SMAD2/3. Therapeutics that antagonize the binding of ActRIIB ligands are in clinical development, but concerns exist about achieving efficacy without off-target effects. To protect striated muscle from harmful ActRIIB signaling, and to reduce the risk of off-target effects, we developed an intervention using recombinant adeno-associated viral vectors (rAAV vectors) that increase expression of Smad7 in skeletal and cardiac muscles. SMAD7 acts as an intracellular negative regulator that prevents SMAD2/3 activation and promotes degradation of ActRIIB complexes. In mouse models of cachexia, rAAV:Smad7 prevented wasting of skeletal muscles and the heart independent of tumor burden and serum levels of procachectic ligands. Mechanistically, rAAV:Smad7 administration abolished SMAD2/3 signaling downstream of ActRIIB and inhibited expression of the atrophy-related ubiquitin ligases MuRF1 and MAFbx. These findings identify muscle-directed Smad7 gene delivery as a potential approach for preventing muscle wasting under conditions where excessive ActRIIB signaling occurs, such as cancer cachexia.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Winbanks
authors.affiliation: Department of Physiology, The University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Kate T
authors.initials: KT
authors.lastname: Murphy
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Bianca C
authors.initials: BC
authors.lastname: Bernardo
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qian
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Patricio V
authors.initials: PV
authors.lastname: Sepulveda
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Claudia
authors.initials: C
authors.lastname: Beyer
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Adam
authors.initials: A
authors.lastname: Hagg
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Thomson
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia. Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Chen
authors.affiliation: Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Walton
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Loveland
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia. Department of Medicine, Monash University, Clayton, Victoria 3800, Australia. Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Julie R
authors.initials: JR
authors.lastname: McMullen
authors.affiliation: Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Buel D
authors.initials: BD
authors.lastname: Rodgers
authors.affiliation: Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia. Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Harrison
authors.affiliation: Department of Physiology, The University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Lynch
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia. Department of Physiology, The University of Melbourne, Melbourne, Victoria 3010, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia. Department of Neurology, The University of Washington School of Medicine, Seattle, WA 98195, USA. paul.gregorevic@bakeridi.edu.au.
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism* / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D000070584:Tripartite Motif Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051906:Smad7 Protein; D000070584:Tripartite Motif Proteins; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B