Transplantation of Human Myoblasts in SCID Mice as a Potential Muscular Model for Myotonic Dystrophy

Abstract

Myotonic dystrophy (DM), the most frequent hereditary myopathy in adults, is characterized clinically by muscle weakness, myotonia, and systemic symptoms. Although the specific genetic basis for DM has been established, less is known about the cellular defects responsible for its pleiotropic manifestations. DM pathogenesis studies are presently limited due to the absence of animal models. In the present study, we transplanted myoblasts of DM patients into the Tibialis anterior of Severe Combined Immunodeficient (SCID) mice to determine whether this approach could reproduce the muscular characteristics of DM. One to 4 months after transplantation, a variable number of innervated human muscle fibers, recognized by an antibody specific for the human dystrophin, were found in the transplanted muscles. The CTG expansion was retained in human muscle fibers as determined by Southern blot analysis. Although the histological characteristics of DM were absent in these fibers, electromyographic recording showed typical myotonic discharges in muscles transplanted with DM myoblasts. The specificity of the myotonic runs was demonstrated by its inhibition by apamin, a drug that specifically blocks DM myotonia. We conclude that transplantation of myoblasts from DM patients into SCID mice represents a potential in vivo model for basic studies of this disease.

Normal growth and regenerating ability of myoblasts from unaffected muscles of facioscapulohumeral muscular dystrophy patients

“…[55][56][57][58] In the present study, human FSHD myoblasts were injected into immunodeficient Rag mice, a validated mouse model for the analysis of muscle regeneration in the context of xenogenic MT. The implantation results we obtained were close to that reported previously [47][48][49] and confirmed that myoblasts prepared from unaffected FSHD muscles, even used at the 6th and 7th passages, take part into in vivo muscle regeneration. The overall number of dystrophin-positive fibers was inferior to that reported previously in immunocompetent models of muscular dystrophies in the context of syngenic or allogenic MT.…”

“…At 1 month after MT, the expression of human proteins validated the implantation of human cells into mouse muscle fibers. 16,[47][48][49] Human dystrophin was observed in all cell-injected muscles, and was absent from muscles injected with a saline solution (Table 3, Figure 5). No significant differences were observed between muscles receiving FSHD or control myoblasts (P40.8).…”

“…The mice were killed 4 weeks after the last series of cell injections, which is a delay compatible with complete mouse muscle regeneration and the expression of donor markers. 16,[47][48][49] The muscles were snap frozen in nitrogen-cooled isopentan and serially sectioned (8 mm) using a cryostat. The participation of human cells in muscle formation was detected by the specific expression of human dystrophin beneath the basement membrane of muscle fibers.…”

Electrophysiological evaluation in myotonic dystrophy: correlation with CTG length expansion

“…Currently explanations include: deficiency of the DM protein kinase 14 ; effect of expanded CTG repeats on neighboring genes [15][16][17][18] ; interference of the mutant DM protein kinase transcripts with others transcripts (trans RNA interference) 19 . Studies that are in progress look for new transgenic models that may more closely resemble clinical DM and that provide also a model for anticipation 20,21 .…”

Dystrophin expression in host muscle following transplantation of muscle precursor cells modified with the phiC31 integrase

“…The cells were transplanted into the TA muscle of immunodeficient severe combined immuno deficient (SCID) mice that tolerate xenograft. 17 The mice were killed a month later. The human cells were able to fuse with the mouse muscle fibers and as shown in Figure 2c and d, eGFP expression was visible in muscle fibers.…”