Fig. 6

Fast muscle innervated by slow motor units via cross-reinnervation surgery acquire resistance to hTDP-43ΔNLS insult, while slow muscle innervated by fast motor units become susceptible. a Representative fluorescence images of NMJs in the hindlimb lateral GC, TA and soleus muscles on the non-surgical and cross-reinnervation surgery sides of rNLS8 mice after 6 wks. off Dox. Axons were immunostained for SV2 and NFL (red) and motor endplates were labelled with BTX-488 (green). Yellow arrows mark intact NMJs (coincident red and green fluorescence), whereas white arrows mark degenerated NMJs. Scale bar: 50 µm. b–d Quantitation of the proportion of NMJs determined to be intact, by fluorescence image analysis as shown in a, in the lateral GC (b; two-way ANOVA, n. s. at each time point), TA (c; two-way ANOVA, *p = 0.019 at 4 wks. off Dox, ****p < 0.0001 at 6 wks. off Dox, **p = 0.0038 at 8 wks. off Dox) and soleus (d; two-way ANOVA, **p = 0.0032 at 6 wks. off Dox; **p = 0.0028 at 8 wks. off Dox) from the cross-reinnervation surgery (S) or non-surgical (N.S.) sides of rNLS8 at the indicated time points after hTDP-43ΔNLS induction. e, f Quantification of Mmp9-positive fast MNs (e; one-way ANOVA, ****p < 0.0001; ***p < 0.001) and SK3-positive slow MNs (f; one-way ANOVA, n. s.) in the lumbar region 3–5 on the non-surgical and surgical sides of rNLS8 mice before and after 8 wks. e or 6 wks. f of hTDP-43ΔNLS expression. g Schematic representation of the principal conclusions from the cross-reinnervation surgery study. SK3-positive slow MNs are resistant to degeneration during hTDP-43ΔNLS insult despite being experimentally forced to reinnervate the fast type, vulnerable TA muscle. Mmp9-positive fast MNs are susceptible to TDP-43 pathology despite being experimentally forced to reinnervate the slow type, resistant soleus muscle