title: Propeptide-mediated inhibition of myostatin increases muscle mass through inhibiting proteolytic pathways in aged mice.
abstract: Mammalian aging is accompanied by a progressive loss of skeletal muscle, a process called sarcopenia. Myostatin, a secreted member of the transforming growth factor-β family of signaling molecules, has been shown to be a potent inhibitor of muscle growth. Here, we examined whether muscle growth could be promoted in aged animals by antagonizing the activity of myostatin through the neutralizing activity of the myostatin propeptide. We show that a single injection of an AAV8 virus expressing the myostatin propeptide induced an increase in whole body weights and all muscles examined within 7 weeks of treatment. Our cellular studies demonstrate that muscle enlargement was due to selective fiber type hypertrophy, which was accompanied by a shift toward a glycolytic phenotype. Our molecular investigations elucidate the mechanism underpinning muscle hypertrophy by showing a decrease in the expression of key genes that control ubiquitin-mediated protein breakdown. Most importantly, we show that the hypertrophic muscle that develops as a consequence of myostatin propeptide in aged mice has normal contractile properties. We suggest that attenuating myostatin signaling could be a very attractive strategy to halt and possibly reverse age-related muscle loss.
authors.affiliation: Molecular and Cellular Medicine, School of Biological Sciences, University of Reading, Whiteknights C ampus.
authors.forename: Henry
authors.initials: H
authors.lastname: Collins-Hooper
authors.affiliation: Venetian Institute of Molecular Medicine, University of Padova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Sartori
authors.affiliation: Veterinary Basic Sciences, Royal Veterinary College, London.
authors.forename: Raymond
authors.initials: R
authors.lastname: Macharia
authors.affiliation: Molecular and Cellular Medicine, School of Biological Sciences, University of Reading, Whiteknights C ampus.
authors.forename: Korntip
authors.initials: K
authors.lastname: Visanuvimol
authors.affiliation: Molecular and Cellular Medicine, School of Biological Sciences, University of Reading, Whiteknights C ampus.
authors.forename: Keith
authors.initials: K
authors.lastname: Foster
authors.affiliation: Health and Exercise Science, University of Hull.
authors.forename: Antonios
authors.initials: A
authors.lastname: Matsakas
authors.affiliation: Molecular and Cellular Medicine, School of Biological Sciences, University of Reading, Whiteknights C ampus.
authors.forename: Hannah
authors.initials: H
authors.lastname: Flasskamp
authors.affiliation: Natural Biosciences, Whiteknights C ampus, Reading.
authors.forename: Steve
authors.initials: S
authors.lastname: Ray
authors.affiliation: Molecular and Cellular Medicine, School of Biological Sciences, University of Reading, Whiteknights C ampus.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Dash
authors.affiliation: Venetian Institute of Molecular Medicine, University of Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
authors.affiliation: Molecular and Cellular Medicine, School of Biological Sciences, University of Reading, Whiteknights C ampus. ketan.patel@reading.ac.uk.
authors.forename: Ketan
authors.initials: K
authors.lastname: Patel
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001835:Body Weight; D005822:Genetic Vectors; D006984:Hypertrophy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000033:anatomy & histology / Q000473:pathology / Q000502:physiology; D055435:Myostatin / Q000037:antagonists & inhibitors* / Q000502:physiology; D010455:Peptides / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
chemical_list: D009124:Muscle Proteins; D055435:Myostatin; D010455:Peptides
keywords: Aging; Mouse; Muscle; Myostatin; Sarcopenia.