Inhibition of activin receptor type IIB increases strength and lifespan in myotubularin-deficient mice. Am J Pathol 2011 Feb;178(2):784-93
Date
02/02/2011Pubmed ID
21281811Pubmed Central ID
PMC3069865DOI
10.1016/j.ajpath.2010.10.035Scopus ID
2-s2.0-79951842509 (requires institutional sign-in at Scopus site) 55 CitationsAbstract
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.
Author List
Lawlor MW, Read BP, Edelstein R, Yang N, Pierson CR, Stein MJ, Wermer-Colan A, Buj-Bello A, Lachey JL, Seehra JS, Beggs AHAuthor
Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Activin Receptors, Type IIAnimals
Behavior, Animal
Body Weight
Forelimb
Gravitation
Hand Strength
Longevity
Mice
Mice, Inbred C57BL
Muscle Strength
Muscle, Skeletal
Myostatin
Protein Tyrosine Phosphatases, Non-Receptor
Recombinant Fusion Proteins
Survival Analysis
