Gd. Sterne et al., NEUROTROPHIN-3-ENHANCED NERVE REGENERATION SELECTIVELY IMPROVES RECOVERY OF MUSCLE-FIBERS EXPRESSING MYOSIN HEAVY-CHAINS 2B, The Journal of cell biology, 139(3), 1997, pp. 709-715
The purpose of this study was to evaluate the effect of neurotrophin 3
(NT-3) enhanced nerve regeneration on the reinnervation of a target m
uscle. Muscle fibers can be classified according to their mechanical p
roperties and myosin heavy chain (MHC) isoform composition. MHC1 conta
ining slow-type and MHC2a or 2b fast-type fibers are normally distribu
ted in a mosaic pattern, their phenotype dictated by motor innervation
. After denervation, all fibers switch to fast-type MHC2b expression a
nd also undergo atrophy resulting in loss of muscle mass. After regene
ration, discrimination between fast and slow fibers returns, but the d
istribution and fiber size change according to the level of reinnervat
ion. In this study, rat gastrocnemius muscles (ipsilateral and contral
ateral to the side of nerve injury) were collected up to 8 mo after ne
rve repair, with or without local delivery of NT-3. The phenotype chan
ges of MHC1, 2a, and 2b were analyzed by immunohistochemistry, and fib
er type proportion, diameter, and grouping were assessed by computeriz
ed image analysis. At 8 mo, the local delivery of NT-3 resulted in sig
nificant improvement in gastrocnemius muscle weight compared with cont
rols (NT-3 group 47%, controls 39% weight of contralateral normal musc
le; 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 mu m, controls 70.8 mu m; P < 0.05) of fast type 2b fibers after
reinnervation. This effect was specific to type 2b fibers; no normaliz
ation was seen in other fiber types. This study indicates that NT-3-en
hanced axonal regeneration has a beneficial effect on the motor target
organ. Also, NT-3 may be specifically affecting a subset of motoneuro
ns that determine type 2b muscle fiber phenotype. As NT-3 was topicall
y applied to cut nerves, our data suggest a discriminating effect of t
he neurotrophin on neuro-muscular interaction. These results would imp
ly that muscle fibers may be differentially responsive to other neurot
rophic factors and indicate the potential clinical role of NT-3 in the
prevention of muscle atrophy after nerve injury.