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J. Cell Biol.,
Volume 139, Number 3, November 3, 1997 709-715
* Blond McIndoe Centre, Queen Victoria Hospital, East Grinstead, West Sussex RH19 3DZ, United Kingdom; The purpose of this study was to evaluate the
effect of neurotrophin 3 (NT-3) enhanced nerve regeneration on the reinnervation of a target muscle. Muscle
fibers can be classified according to their mechanical
properties and myosin heavy chain (MHC) isoform composition. MHC1 containing slow-type and MHC2a
or 2b fast-type fibers are normally distributed in a mosaic pattern, their phenotype dictated by motor innervation. After denervation, all fibers switch to fast-type
MHC2b expression and also undergo atrophy resulting in loss of muscle mass. After regeneration, discrimination between fast and slow fibers returns, but the distribution and fiber size change according to the level of
reinnervation.
In this study, rat gastrocnemius muscles (ipsilateral
and contralateral to the side of nerve injury) were collected up to 8 mo after nerve repair, with or without local delivery of NT-3. The phenotype changes of MHC1,
2a, and 2b were analyzed by immunohistochemistry, and fiber type proportion, diameter, and grouping were
assessed by computerized image analysis. At 8 mo, the
local delivery of NT-3 resulted in significant improvement in gastrocnemius muscle weight compared with
controls (NT-3 group 47%, controls 39% weight of contralateral normal muscle; P < 0.05). NT-3 delivery resulted in a significant increase in the proportion (NT-3
43.3%, controls 35.7%; P < 0.05) and diameter (NT-3
87.8 µm, controls 70.8 µm; P < 0.05) of fast type 2b fibers after reinnervation. This effect was specific to type
2b fibers; no normalization was seen in other fiber
types.
This study indicates that NT-3-enhanced axonal regeneration has a beneficial effect on the motor target
organ. Also, NT-3 may be specifically affecting a subset
of motoneurons that determine type 2b muscle fiber
phenotype. As NT-3 was topically applied to cut
nerves, our data suggest a discriminating effect of the neurotrophin on neuro-muscular interaction. These results would imply that muscle fibers may be differentially responsive to other neurotrophic factors and indicate the potential clinical role of NT-3 in the prevention
of muscle atrophy after nerve injury.
Department of
Biochemistry, Charing Cross and Westminster Medical School, London W6 8RF, United Kingdom; and § Department of Plastic
and Reconstructive Surgery, University College, London W1P 7LD, United Kingdom
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