Faculty Collaboration Database

Differential muscle hypertrophy is associated with satellite cell numbers and Akt pathway activation following activin type IIB receptor inhibition in Mtm1 p.R69C mice. Am J Pathol 2014 Jun;184(6):1831-42

Date

04/15/2014

Pubmed ID

24726641

Pubmed Central ID

PMC4044712

DOI

10.1016/j.ajpath.2014.03.003

Scopus ID

2-s2.0-84901020192 (requires institutional sign-in at Scopus site)   27 Citations

Abstract

X-linked myotubular myopathy is a congenital myopathy caused by deficiency of myotubularin. Patients often present with severe perinatal weakness, requiring mechanical ventilation to prevent death from respiratory failure. We recently reported that an activin receptor type IIB inhibitor produced hypertrophy of type 2b myofibers and modest increases of strength and life span in the severely myopathic Mtm1δ4 mouse model of X-linked myotubular myopathy. We have now performed a similar study in the less severely symptomatic Mtm1 p.R69C mouse in hopes of finding greater treatment efficacy. Activin receptor type IIB inhibitor treatment of Mtm1 p.R69C animals produced behavioral and histological evidence of hypertrophy in gastrocnemius muscles but not in quadriceps or triceps. The ability of the muscles to respond to activin receptor type IIB inhibitor treatment correlated with treatment-induced increases in satellite cell number and several muscle-specific abnormalities of hypertrophic signaling. Treatment-responsive Mtm1 p.R69C gastrocnemius muscles displayed lower levels of phosphorylated ribosomal protein S6 and higher levels of phosphorylated eukaryotic elongation factor 2 kinase than were observed in Mtm1 p.R69C quadriceps muscle or in muscles from wild-type littermates. Hypertrophy in the Mtm1 p.R69C gastrocnemius muscle was associated with increased levels of phosphorylated ribosomal protein S6. Our findings indicate that muscle-, fiber type-, and mutation-specific factors affect the response to hypertrophic therapies that will be important to assess in future therapeutic trials.

Author List

Lawlor MW, Viola MG, Meng H, Edelstein RV, Liu F, Yan K, Luna EJ, Lerch-Gaggl A, Hoffmann RG, Pierson CR, Buj-Bello A, Lachey JL, Pearsall S, Yang L, Hillard CJ, Beggs AH

Authors

Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of Wisconsin
Ke Yan PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin

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

Activin Receptors, Type II
Animals
Disease Models, Animal
Mice
Mice, Mutant Strains
Muscle Proteins
Muscle, Skeletal
Myopathies, Structural, Congenital
Protein Tyrosine Phosphatases, Non-Receptor
Proto-Oncogene Proteins c-akt
Satellite Cells, Skeletal Muscle
Signal Transduction