Reduced TrkB-mediated signaling results in altered neuromuscular synaptic structure, impaired neurotransmission and muscle weakness
Kulakowski, Scott A.
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Altered skeletal muscle innervation is an underlying cause of muscle atrophy during aging, but the mechanisms controlling these age-dependent impairments in innervations are unknown. TrkB and the ligands, BDNF and NT-4/5, are localized to the neuromuscular junction. TrkB-mediated signaling maintains normal AChR clustering and potentiates neuromuscular junction transmission in young rodents. Thus, we are interested in whether reduced TrkB-mediated signaling at the neuromuscular junction is associated with muscle aging. We have previously shown that TrkB expression at the neuromuscular junction is reduced during aging and is associated with age-related changes in synaptic structure. Here, we ask whether synaptic structure, contractile properties or neurotransmission is impaired in the soleus muscle of 6-8 month old TrkB+/-B6;129S2- Ntrk 2tmlBbd /J mice compared to wild-type mice. These structural changes appear to influence synaptic function, since neurotransmission failure was significantly increased to 76.8 ± 6.7 % after 5 min. of fatiguing contractions in TrkB+/- mice compared to 68.7 ± 5.7 % in wild-type controls. Specific muscle force (P o ) was significantly decreased from 20.6 ± 1.5 N/cm 2 in wild-type to 15.4 ± 1.2 N/cm 2 in TrkB +/- mice, though no change was seen in twitch force, time to peak twitch force, or 1⁄2 relaxation time. Structural changes within the neuromuscular junction include increased AChR fragmentation (2.8 ± 0.2 clusters in WT mice to 5.0 ± 0.4 clusters in TrkB +/- littermates) and endplate expansion (AChR area from 469 ± 17 μm 2 in WT to 552 ± 22 μm 2 in TrkB +/-). Together, these results suggest that TrkB-mediated signaling at the neuromuscular junction may be necessary for the normal maintenance of AChR structure, neurotransmission and muscle function.