Faculty Collaboration Database

Myotubularin-deficient myoblasts display increased apoptosis, delayed proliferation, and poor cell engraftment. Am J Pathol 2012 Sep;181(3):961-8

Date

07/31/2012

Pubmed ID

22841819

Pubmed Central ID

PMC3432426

DOI

10.1016/j.ajpath.2012.05.016

Scopus ID

2-s2.0-84865267643 (requires institutional sign-in at Scopus site)   34 Citations

Abstract

X-linked myotubular myopathy is a severe congenital myopathy caused by deficiency of the lipid phosphatase, myotubularin. Recent studies of human tissue and animal models have discovered structural and physiological abnormalities in myotubularin-deficient muscle, but the impact of myotubularin deficiency on myogenic stem cells within muscles is unclear. In the present study, we evaluated the viability, proliferative capacity, and in vivo engraftment of myogenic cells obtained from severely symptomatic (Mtm1δ4) myotubularin-deficient mice. Mtm1δ4 muscle contains fewer myogenic cells than wild-type (WT) littermates, and the number of myogenic cells decreases with age. The behavior of Mtm1δ4 myoblasts is also abnormal, because they engraft poorly into C57BL/6/Rag1null/mdx5cv mice and display decreased proliferation and increased apoptosis compared with WT myoblasts. Evaluation of Mtm1δ4 animals at 21 and 42 days of life detected fewer satellite cells in Mtm1δ4 muscle compared with WT littermates, and the decrease in satellite cells correlated with progression of disease. In addition, analysis of WT and Mtm1δ4 regeneration after injury detected similar abnormalities of satellite cell function, with fewer satellite cells, fewer dividing cells, and increased apoptotic cells in Mtm1δ4 muscle. These studies demonstrate specific abnormalities in myogenic cell number and behavior that may relate to the progression of disease in myotubularin deficiency, and may also be used to develop in vitro assays by which novel treatment strategies can be assessed.

Author List

Lawlor MW, Alexander MS, Viola MG, Meng H, Joubert R, Gupta V, Motohashi N, Manfready RA, Hsu CP, Huang P, Buj-Bello A, Kunkel LM, Beggs AH, Gussoni E

Author

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

Animals
Apoptosis
Cell Count
Cell Proliferation
Cell Survival
Disease Progression
Humans
Mice
Mice, Inbred C57BL
Muscle, Skeletal
Myoblasts
PAX7 Transcription Factor
Protein Tyrosine Phosphatases, Non-Receptor
Satellite Cells, Skeletal Muscle