title: Myotubularin-deficient myoblasts display increased apoptosis, delayed proliferation, and poor cell engraftment.
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.
authors: Division of Genetics and the Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
authors: Michael W
authors: MW
authors: Lawlor
authors: Matthew S
authors: MS
authors: Alexander
authors: Marissa G
authors: MG
authors: Viola
authors: Hui
authors: H
authors: Meng
authors: Romain
authors: R
authors: Joubert
authors: Vandana
authors: V
authors: Gupta
authors: Norio
authors: N
authors: Motohashi
authors: Richard A
authors: RA
authors: Manfready
authors: Cynthia P
authors: CP
authors: Hsu
authors: Ping
authors: P
authors: Huang
authors: Anna
authors: A
authors: Buj-Bello
authors: Louis M
authors: LM
authors: Kunkel
authors: Alan H
authors: AH
authors: Beggs
authors: Emanuela
authors: E
authors: Gussoni
mesh_terms: D000818:Animals; D017209:Apoptosis; D002452:Cell Count; D049109:Cell Proliferation; D002470:Cell Survival; D018450:Disease Progression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000293:injuries / Q000473:pathology; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation*; D051763:PAX7 Transcription Factor / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000172:deficiency* / Q000378:metabolism; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism / Q000473:pathology
chemical_list: D051763:PAX7 Transcription Factor; C497322:Pax7 protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin