Functional overloading of dystrophic mice enhances muscle-derived stem cell contribution to muscle contractile capacity.
OBJECTIVE
To evaluate the effect of functional overloading on the transplantation of muscle derived stem cells (MDSCs) into dystrophic muscle and the ability of transplanted cells to increase dystrophic muscle's ability to resist overloading-induced weakness.


METHODS
Cross-sectional.


METHODS
Laboratory.


METHODS
Male mice (N=10) with a dystrophin gene mutation.


METHODS
MDSCs were intramuscularly transplanted into the extensor digitorum longus muscle (EDL). Functional overloading of the EDL was performed by surgical ablation of the EDL's synergist.


METHODS
The total number of dystrophin-positive fibers/cross-section (as a measure of stem cell engraftment), the average number of CD31+ cells (as a measure of capillarity), and in vitro EDL contractile strength. Independent t tests were used to investigate the effect of overloading on engraftment, capillarity, and strength. Paired t tests were used to investigate the effect of MDSC engraftment on strength and capillarity.


RESULTS
MDSC transplantation protects dystrophic muscles against overloading-induced weakness (specific twitch force: control 4.5N/cm2+/-2.3; MDSC treated 7.9N/cm2+/-1.4) (P=.02). This improved force production following overloading is concomitant with an increased regeneration by transplanted MDSCs (MDSC: 26.6+/-20.2 dystrophin-positive fibers/cross-section; overloading + MDSC: 170.6+/-130.9 dystrophin-positive fibers/cross-section [P=.03]). Overloading-induced increases in skeletal muscle capillarity is significantly correlated with increased MDSC engraftment (R2=.80, P=.01).


CONCLUSIONS
These findings suggest that the functional contribution of transplanted MDSCs may rely on activity-dependent mechanisms, possibly mediated by skeletal muscle vascularity. Rehabilitation modalities may play an important role in the development of stem cell transplantation strategies for the treatment of muscular dystrophy.
Ambrosio
Fabrisia
F
Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA 15213, USA. ambrosiof@upmc.edu
Ferrari
Ricardo J
RJ
Fitzgerald
G Kelley
GK
Carvell
George
G
Boninger
Michael L
ML
Huard
Johnny
J
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016189:Dystrophin / Q000008:administration & dosage / Q000172:deficiency / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects*; D009137:Muscular Dystrophy, Animal / Q000628:therapy*; D033581:Stem Cell Transplantation
D016189:Dystrophin