title: Syngeneic Myoblast Transplantation Improves Muscle Function in a Murine Model of X-Linked Myotubular Myopathy.
abstract: X-linked myotubular myopathy (XLMTM) is an isogenic muscle disease characterized by progressive wasting of skeletal muscle, weakness, and premature death of affected male offspring. Recently, the XLMTM gene knock-in mouse, Mtm1 p.R69C, was found to have a similar phenotype as the Mtm1 gene mutation in humans (e.g., central nucleation of small myofibers, attenuated muscle strength, and motor unit potentials). Using this rodent model, we investigated whether syngeneic cell therapy could mitigate muscle weakness. Donor skeletal muscle-derived myoblasts were isolated from C57BL6 wild-type (WT) and Mtm1 p.R69C (KI) mice for transplantation into the gastrocnemius muscle of recipient KI mice. Initial experiments demonstrated that donor skeletal muscle-derived myoblasts from WT and KI mice remained in the gastrocnemius muscle of the recipient KI mouse for up to 4 weeks posttransplantation. KI mice receiving syngeneic skeletal muscle-derived myoblasts displayed an increase in skeletal muscle mass, augmented force generation, and increased nerve-evoked skeletal muscle action potential amplitude. Taken together, these results support our hypothesis that syngeneic cell therapy may potentially be used to ameliorate muscle weakness and delay the progression of XLMTM, as application expands to other muscles.
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, USA.
authors.forename: Hyun Ju
authors.initials: HJ
authors.lastname: Lim
authors.forename: Sunyoung
authors.initials: S
authors.lastname: Joo
authors.forename: Seh-Hoon
authors.initials: SH
authors.lastname: Oh
authors.forename: John D
authors.initials: JD
authors.lastname: Jackson
authors.forename: Delrae M
authors.initials: DM
authors.lastname: Eckman
authors.forename: Tiffaney M
authors.initials: TM
authors.lastname: Bledsoe
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Pierson
authors.forename: Martin K
authors.initials: MK
authors.lastname: Childers
authors.forename: Anthony
authors.initials: A
authors.lastname: Atala
authors.forename: James J
authors.initials: JJ
authors.lastname: Yoo
mesh_terms: D000200:Action Potentials; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D005838:Genotype; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology; D017570:MyoD Protein / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000637:transplantation*; D051787:Myogenic Regulatory Factor 5 / Q000378:metabolism; D020914:Myopathies, Structural, Congenital / Q000628:therapy*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics
chemical_list: C497418:Myf5 protein, mouse; D017570:MyoD Protein; D051787:Myogenic Regulatory Factor 5; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin