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Treatment with ActRIIB-mFc Produces Myofiber Growth and Improves Lifespan in the Acta1 H40Y Murine Model of Nemaline Myopathy. Am J Pathol 2016 Jun;186(6):1568-81

Date

04/23/2016

Pubmed ID

27102768

Pubmed Central ID

PMC4901141

DOI

10.1016/j.ajpath.2016.02.008

Scopus ID

2-s2.0-84969848977   14 Citations

Abstract

Nemaline myopathies (NMs) are a group of congenital muscle diseases caused by mutations in at least 10 genes and associated with a range of clinical symptoms. NM is defined on muscle biopsy by the presence of cytoplasmic rod-like structures (nemaline rods) composed of cytoskeletal material. Myofiber smallness is also found in many cases of NM and may represent a cause of weakness that can be counteracted by treatment. We have used i.p. injection of activin type IIB receptor (ActRIIB)-mFc (an inhibitor of myostatin signaling) to promote hypertrophy and increase strength in our prior murine work; we therefore tested whether ActRIIB-mFc could improve weakness in NM mice through myofiber hypertrophy. We report a study of ActRIIB-mFc treatment in the Acta1 H40Y mouse model of NM. Treatment of Acta1 H40Y mice produced significant increases in body mass, muscle mass, quadriceps myofiber size, and survival, but other measurements of strength (forelimb grip strength, ex vivo measurements of contractile function) did not improve. Our studies also identified that the complications of urethral obstruction are associated with mortality in male hemizygote Acta1 H40Y mice. The incidence of urethral obstruction and histologic evidence of chronic obstruction (inflammation) were significantly lower in Acta1 H40Y mice that had been treated with ActRIIB-mFc. ActRIIB-mFc treatment produces a mild benefit to the disease phenotype in Acta1 H40Y mice.

Author List

Tinklenberg J, Meng H, Yang L, Liu F, Hoffmann RG, Dasgupta M, Allen KP, Beggs AH, Hardeman EC, Pearsall RS, Fitts RH, Lawlor MW

Authors

Kenneth Paul Allen DVM Associate Professor in the Research Office department at Medical College of Wisconsin
Robert Fitts PhD Professor in the Biological Sciences department at Marquette University
Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Activin Receptors, Type II
Animals
Blotting, Western
Disease Models, Animal
Male
Mice
Mice, Mutant Strains
Muscle, Skeletal
Myofibrils
Myopathies, Nemaline