Myogenic growth factors can decrease extraocular muscle force generation: a potential biological approach to the treatment of strabismus.
OBJECTIVE
Future pharmacologic treatment of strabismus may be optimized if drugs that are less potentially toxic to patients can be developed. Prior studies have shown that direct injection of extraocular muscles (EOMs) with insulin growth factor or fibroblast growth factor results in significant increases in the generation of EOM force. The purpose of this study was to examine the morphometric and physiological effects of direct EOM injection with the growth factors BMP4, TGFbeta1, Shh, and Wnt3A.


METHODS
One superior rectus muscle of normal adult rabbits was injected with BMP4, TGFbeta1, Shh, or Wnt3A. The contralateral muscle was injected with an equal volume of saline to serve as a control. After 1 week, the animals were euthanatized, and both superior rectus muscles were removed and assayed physiologically. The muscles were stimulated at increasing frequencies to determine force generation. A separate group of treated and control superior rectus muscles were examined histologically for alterations in total muscle cross-sectional area and myosin heavy chain isoform (MyHC) composition.


RESULTS
One week after a single injection of BMP4, TGFbeta1, Shh, or Wnt3A, all treated muscles showed significant decreases in generation of force compared with control muscles. BMP4, TGFbeta1, Shh, and Wnt3A significantly decreased the mean myofiber cross-sectional area of fast MyHC-positive myofibers. BMP4 resulted in a conversion of fast-to-slow myofibers and a significant decrease in the percentage of developmental and neonatal MyHC-positive myofibers. Alterations in mean cross-sectional area and proportion of MyHCs were seen after injection with TGFbeta1, Shh, and Wnt3A. TGFbeta1 and BMP4 injections resulted in increased Pax7-positive satellite cells, whereas BMP4, TGFbeta1, and Wnt3A resulted in a decrease in MyoD-positive satellite cells.


CONCLUSIONS
These results suggest that, rather than using toxins or immunotoxins, a more biological approach to decrease muscle strength is possible and demonstrate the potential utility of myogenic signaling factors for decreasing EOM strength. Ongoing drug-delivery studies will elucidate means of extending treatment effect to make such agents clinically useful.
Anderson
Brian C
BC
Department of Ophthalmology, University of Minnesota, 2001 6th Street SE, Minneapolis, MN 55455, USA.
Christiansen
Stephen P
SP
McLoon
Linda K
LK
D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D053823:Hedgehog Proteins / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D007273:Injections, Intramuscular; D009119:Muscle Contraction; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D017570:MyoD Protein / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism; D009801:Oculomotor Muscles / Q000187:drug effects* / Q000378:metabolism; D051763:PAX7 Transcription Factor / Q000378:metabolism; D011817:Rabbits; D013285:Strabismus / Q000188:drug therapy; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D051153:Wnt Proteins / Q000494:pharmacology*; D060508:Wnt3 Protein
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D053823:Hedgehog Proteins; D017570:MyoD Protein; D051763:PAX7 Transcription Factor; D053773:Transforming Growth Factor beta1; D051153:Wnt Proteins; D060508:Wnt3 Protein; D018995:Myosin Heavy Chains