Myotubularin-Deficient Myoblasts Display Increased Apoptosis, Delayed Proliferation, and Poor Cell Engraftment

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 (Mtm1 delta 4) myotubularin-deficient mice. Mtm1 delta 4 muscle contains fewer myogenic cells than wild-type (WT) littermates, and the number of myogenic cells decreases with age. The behavior of Mtm1 delta 4 myoblasts is also abnormal, because they engraft poorly into C57BL/6/Rag1null/mdx5cv mice and display decreased proliferation and increased apoptosis compared with WE myoblasts. Evaluation of Mtm1 delta 4 animals at 21 and 42 days of life detected fewer satellite cells in Mtm1 delta 4 muscle compared with WE littermates, and the decrease in satellite cells correlated with progression of disease. In addition, analysis of WE and Mtm1 delta 4 regeneration after injury detected similar abnormalities of satellite cell function, with fewer satellite cells, fewer dividing cells, and increased apoptotic cells in Mtm1 delta 4 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. (Am J Pathol 2012, 181:961-968 http://dx.doi.org/10.1016/j.ajpath.2012.05.016)