Treatment with ActRIIB-mFc Produces Myofiber Growth and Improves Lifespan in the Acta1 H40Y Murine Model of Nemaline Myopathy.
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.
Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
Jennifer
J
Tinklenberg
Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.
Hui
H
Meng
Department of Biomedical Engineering, University of Florida, Gainesville, Florida.
Lin
L
Yang
Department of Biomedical Engineering, University of Florida, Gainesville, Florida.
Fujun
F
Liu
Quantitative Health Sciences Section, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.
Raymond G
RG
Hoffmann
Quantitative Health Sciences Section, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.
Mahua
M
Dasgupta
Biomedical Resource Center, Office of Research, Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin.
Kenneth P
KP
Allen
Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Alan H
AH
Beggs
Neuromuscular and Regenerative Medicine Unity, Department of Anatomy, University of New South Wales, Sydney, Australia.
Edna C
EC
Hardeman
Acceleron Pharma Inc., Boston, Massachusetts.
R Scott
RS
Pearsall
Department of Biological Sciences, Marquette University, Milwaukee, Wisconsin.
Robert H
RH
Fitts
Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address: mlawlor@mcw.edu.
Michael W
MW
Lawlor
D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors*; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D009210:Myofibrils / Q000187:drug effects* / Q000473:pathology; D017696:Myopathies, Nemaline / Q000473:pathology*
D030301:Activin Receptors, Type II; C425584:activin receptor type II-B