title: Integrated expression analysis of muscle hypertrophy identifiesAsb2as a negative regulator of muscle mass.
abstract: The transforming growth factor-β (TGF-β) signaling network is a critical regulator of skeletal muscle mass and function and, thus, is an attractive therapeutic target for combating muscle disease, but the underlying mechanisms of action remain undetermined. We report that follistatin-based interventions (which modulate TGF-β network activity) can promote muscle hypertrophy that ameliorates aging-associated muscle wasting. However, the muscles of old sarcopenic mice demonstrate reduced response to follistatin compared with healthy young-adult musculature. Quantitative proteomic and transcriptomic analyses of young-adult muscles identified a transcription/translation signature elicited by follistatin exposure, which included repression of ankyrin repeat and SOCS box protein 2 (Asb2). Increasing expression of ASB2 reduced muscle mass, thereby demonstrating thatAsb2is a TGF-β network-responsive negative regulator of muscle mass. In contrast to young-adult muscles, sarcopenic muscles do not exhibit reduced ASB2 abundance with follistatin exposure. Moreover, preventing repression of ASB2 in young-adult muscles diminished follistatin-induced muscle hypertrophy. These findings provide insight into the program of transcription and translation events governing follistatin-mediated adaptation of skeletal muscle attributes and identifyAsb2as a regulator of muscle mass implicated in the potential mechanistic dysfunction between follistatin-mediated muscle growth in young and old muscles.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Davey
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Kevin I
authors.initials: KI
authors.lastname: Watt
authors.affiliation: Charles Perkins Centre, School of Molecular Bioscience, The University of Sydney, Sydney, Australia.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Parker
authors.affiliation: Charles Perkins Centre, School of Molecular Bioscience, The University of Sydney, Sydney, Australia.
authors.forename: Rima
authors.initials: R
authors.lastname: Chaudhuri
authors.affiliation: National Institute of Arthritis Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, Maryland, USA; Department of Physiology, The University of Melbourne, Melbourne, Australia.
authors.forename: James G
authors.initials: JG
authors.lastname: Ryall
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Louise
authors.initials: L
authors.lastname: Cunningham
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qian
authors.affiliation: National Institute of Arthritis Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, Maryland, USA.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Sartorelli
authors.affiliation: Venetian Institute of Molecular Medicine, The University of Padova, Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
authors.affiliation: Department of Neurology, The University of Washington, Seattle, Washington, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Chamberlain
authors.affiliation: Charles Perkins Centre, School of Molecular Bioscience, The University of Sydney, Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia.
authors.forename: David E
authors.initials: DE
authors.lastname: James
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Department of Physiology, The University of Melbourne, Melbourne, Australia; Department of Neurology, The University of Washington, Seattle, Washington, USA; Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic