title: Evaluation of follistatin as a therapeutic in models of skeletal muscle atrophy associated with denervation and tenotomy.
abstract: Follistatin is an inhibitor of TGF-β superfamily ligands that repress skeletal muscle growth and promote muscle wasting. Accordingly, follistatin has emerged as a potential therapeutic to ameliorate the deleterious effects of muscle atrophy. However, it remains unclear whether the anabolic effects of follistatin are conserved across different modes of non-degenerative muscle wasting. In this study, the delivery of a recombinant adeno-associated viral vector expressing follistatin (rAAV:Fst) to the hind-limb musculature of mice two weeks prior to denervation or tenotomy promoted muscle hypertrophy that was sufficient to preserve muscle mass comparable to that of untreated sham-operated muscles. However, administration of rAAV:Fst to muscles at the time of denervation or tenotomy did not prevent subsequent muscle wasting. Administration of rAAV:Fst to innervated or denervated muscles increased protein synthesis, but markedly reduced protein degradation only in innervated muscles. Phosphorylation of the signalling proteins mTOR and S6RP, which are associated with protein synthesis, was increased in innervated muscles administered rAAV:Fst, but not in treated denervated muscles. These results demonstrate that the anabolic effects of follistatin are influenced by the interaction between muscle fibres and motor nerves. These findings have important implications for understanding the potential efficacy of follistatin-based therapies for non-degenerative muscle wasting.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.|Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood 3125, Australia.|Department of Physiology, Monash University, Clayton, 3800, Australia.
authors.forename: Patricio V
authors.initials: PV
authors.lastname: Sepulveda
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood 3125, Australia.
authors.forename: Séverine
authors.initials: S
authors.lastname: Lamon
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.
authors.forename: Adam
authors.initials: A
authors.lastname: Hagg
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Thomson
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Winbanks
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qian
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood 3125, Australia.
authors.forename: Clinton R
authors.initials: CR
authors.lastname: Bruce
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood 3125, Australia.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Russell
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.|Dept. of Neurology, The University of Washington School of Medicine, Seattle 98195, USA.|Dept. of Biochemistry and Molecular Biology, Monash University, Clayton, 3800, Australia.|Dept. of Physiology, The University of Melbourne, 3010, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
mesh_terms: D000818:Animals; D003714:Denervation / Q000009:adverse effects*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D038681:Follistatin / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006984:Hypertrophy; D051379:Mice; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000209:etiology* / Q000473:pathology* / Q000628:therapy; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D058971:Tenotomy / Q000009:adverse effects*; D014161:Transduction, Genetic
chemical_list: D038681:Follistatin; D058570:TOR Serine-Threonine Kinases