title: Inhibition of activin receptor type IIB increases strength and lifespan in myotubularin-deficient mice.
abstract: X-linked myotubular myopathy (XLMTM) is a congenital disorder caused by deficiency of the lipid phosphatase, myotubularin. Patients with XLMTM often have severe perinatal weakness that requires mechanical ventilation to prevent death from respiratory failure. Muscle biopsy specimens from patients with XLMTM exhibit small myofibers with central nuclei and central aggregations of organelles in many cells. It was postulated that therapeutically increasing muscle fiber size would cause symptomatic improvement in myotubularin deficiency. Recent studies have elucidated an important role for the activin-receptor type IIB (ActRIIB) in regulation of muscle growth and have demonstrated that ActRIIB inhibition results in significant muscle hypertrophy. To evaluate whether promoting muscle hypertrophy can attenuate symptoms resulting from myotubularin deficiency, the effect of ActRIIB-mFC treatment was determined in myotubularin-deficient (Mtm1δ4) mice. Compared with wild-type mice, untreated Mtm1δ4 mice have decreased body weight, skeletal muscle hypotrophy, and reduced survival. Treatment of Mtm1δ4 mice with ActRIIB-mFC produced a 17% extension of lifespan, with transient increases in weight, forelimb grip strength, and myofiber size. Pathologic analysis of Mtm1δ4 mice during treatment revealed that ActRIIB-mFC produced marked hypertrophy restricted to type 2b myofibers, which suggests that oxidative fibers in Mtm1δ4 animals are incapable of a hypertrophic response in this setting. These results support ActRIIB-mFC as an effective treatment for the weakness observed in myotubularin deficiency.
authors.affiliation: Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lawlor
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Read
authors.forename: Rachel
authors.initials: R
authors.lastname: Edelstein
authors.forename: Nicole
authors.initials: N
authors.lastname: Yang
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Pierson
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Stein
authors.forename: Ariana
authors.initials: A
authors.lastname: Wermer-Colan
authors.forename: Anna
authors.initials: A
authors.lastname: Buj-Bello
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Lachey
authors.forename: Jasbir S
authors.initials: JS
authors.lastname: Seehra
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
mesh_terms: D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D005552:Forelimb / Q000187:drug effects / Q000502:physiology; D006112:Gravitation; D018737:Hand Strength / Q000502:physiology; D008136:Longevity / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053580:Muscle Strength / Q000187:drug effects / Q000502:physiology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D055435:Myostatin / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000172:deficiency* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D016019:Survival Analysis
chemical_list: D055435:Myostatin; D011993:Recombinant Fusion Proteins; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin