title: Adeno-associated virus-8-mediated intravenous transfer of myostatin propeptide leads to systemic functional improvements of slow but not fast muscle.
abstract: Myostatin is a member of the transformating growth factor-beta (TGF-beta) superfamily of proteins and is produced almost exclusively in skeletal muscle tissue, where it is secreted and circulates as a serum protein. Myostatin acts as a negative regulator of muscle mass through the canonical SMAD2/3/4 signaling pathway. Naturally occurring myostatin mutants exhibit a 'double muscling' phenotype in which muscle mass is dramatically increased as a result of both hypertrophy and hyperplasia. Myostatin is naturally inhibited by its own propeptide; therefore, we assessed the impact of adeno-associated virus-8 (AAV8) myostatin propeptide vectors when systemically introduced in MF-1 mice. We noted a significant systemic increase in muscle mass in both slow and fast muscle phenotypes, with no evidence of hyperplasia; however, the nuclei-to- cytoplasm ratio in all myofiber types was significantly reduced. An increase in muscle mass in slow (soleus) muscle led to an increase in force output; however, an increase in fast (extensor digitorum longus [EDL]) muscle mass did not increase force output. These results suggest that the use of gene therapeutic regimens of myostatin inhibition for age-related or disease-related muscle loss may have muscle-specific effects.
authors.affiliation: SWAN Institute of Biomedical and Life Sciences, School of Biological Sciences, Royal Holloway-University of London, Egham, UK.
authors.forename: Keith
authors.initials: K
authors.lastname: Foster
authors.forename: Ian R
authors.initials: IR
authors.lastname: Graham
authors.forename: Anthony
authors.initials: A
authors.lastname: Otto
authors.forename: Helen
authors.initials: H
authors.lastname: Foster
authors.forename: Capucine
authors.initials: C
authors.lastname: Trollet
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Yaworsky
authors.forename: Frank S
authors.initials: FS
authors.lastname: Walsh
authors.forename: Dale
authors.initials: D
authors.lastname: Bickham
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Curtin
authors.forename: Susannah L
authors.initials: SL
authors.lastname: Kawar
authors.forename: Ketan
authors.initials: K
authors.lastname: Patel
authors.forename: George
authors.initials: G
authors.lastname: Dickson
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D000229:Dependovirus / Q000378:metabolism*; D018014:Gene Transfer Techniques; D006965:Hyperplasia; D006984:Hypertrophy; D007275:Injections, Intravenous; D051379:Mice; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D055435:Myostatin / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D010455:Peptides / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D011498:Protein Precursors / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D032496:Satellite Cells, Skeletal Muscle / Q000187:drug effects / Q000473:pathology
chemical_list: D055435:Myostatin; D010455:Peptides; D011498:Protein Precursors