title: Muscle hypertrophy induced by myostatin inhibition accelerates degeneration in dysferlinopathy.
abstract: Myostatin is a secreted signaling molecule that normally acts to limit muscle growth. As a result, there is extensive effort directed at developing drugs capable of targeting myostatin to treat patients with muscle loss. One potential concern with this therapeutic approach in patients with muscle degenerative diseases like muscular dystrophy is that inducing hypertrophy may increase stress on dystrophic fibers, thereby accelerating disease progression. To investigate this possibility, we examined the effect of blocking the myostatin pathway in dysferlin-deficient (Dysf(-/-)) mice, in which membrane repair is compromised, either by transgenic expression of follistatin in skeletal muscle or by systemic administration of the soluble form of the activin type IIB receptor (ACVR2B/Fc). Here, we show that myostatin inhibition by follistatin transgene expression in Dysf(-/-) mice results in early improvement in histopathology but ultimately exacerbates muscle degeneration; this effect was not observed in dystrophin-deficient (mdx) mice, suggesting that accelerated degeneration induced by follistatin transgene expression is specific to mice lacking dysferlin. Dysf(-/-) mice injected with ACVR2B/Fc showed significant increases in muscle mass and amelioration of fibrotic changes normally seen in 8-month-old Dysf(-/-) mice. Despite these potentially beneficial effects, ACVR2B/Fc treatment caused increases in serum CK levels in some Dysf(-/-) mice, indicating possible muscle damage induced by hypertrophy. These findings suggest that depending on the disease context, inducing muscle hypertrophy by myostatin blockade may have detrimental effects, which need to be weighed against the potential gains in muscle growth and decreased fibrosis.
authors.affiliation: Department of Molecular Biology and Genetics and.
authors.forename: Yun-Sil
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Molecular Biology and Genetics and.
authors.forename: Adam
authors.initials: A
authors.lastname: Lehar
authors.affiliation: Department of Molecular Biology and Genetics and.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Sebald
authors.affiliation: Department of Physiology, Perelman School of Medicine and.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Medicine, Section of Cardiology and.
authors.forename: Kayleigh A
authors.initials: KA
authors.lastname: Swaggart
authors.affiliation: Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, 725 North Wolfe Street, PCTB 803, Baltimore, MD 21205, USA.
authors.forename: C Conover
authors.initials: CC
authors.lastname: Talbot
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Pytel
authors.affiliation: Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Elisabeth R
authors.initials: ER
authors.lastname: Barton
authors.affiliation: Department of Medicine, Section of Cardiology and.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: McNally
authors.affiliation: Department of Molecular Biology and Genetics and sjlee@jhmi.edu.
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D000073939:Dysferlin; D038681:Follistatin / Q000235:genetics / Q000494:pharmacology; D055786:Gene Knockout Techniques; D006984:Hypertrophy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D055435:Myostatin / Q000037:antagonists & inhibitors*; D019076:Transgenes
chemical_list: C497505:Dysf protein, mouse; D000073939:Dysferlin; D038681:Follistatin; D008565:Membrane Proteins; C525912:Mstn protein, mouse; D055435:Myostatin