Fig. 5

Suppressing the hTDP- 43ΔNLS transgene does not reverse muscle atrophy and dysfunction despite apparent muscle re-innervation in Tg aged mice. a-b Pictures of the phenotype of a representative young (a) and aged (b) rNLS8 mouse after 6 weeks of hTDP-43ΔNLS expression followed by 10 wk of suppression. Note that the young mouse splays its limbs normally, while the aged mouse is still clasping. c-e Representative pictures of muscle fibers from TAs of young (c) and aged (d) rNLS8 mice after 6 wks of transgene expression and 12 wks of subsequent suppression, stained with succinate dehydrogenase. Scale bars = 100 μm. e In both young and aged rNLS8 mice, average cross sectional fiber area in the TA muscle decreases during disease (6 wks off Dox, grey bar), reflecting muscle atrophy after denervation. However, in the young rNLS8 mice, after transgene suppression, the TA is re-innervated, and the average fiber size returns to baseline levels. Conversely, in the aged rNLS8 mice, despite apparent muscle re-innervation, the muscle remains significantly smaller than nTg controls. Mean ± SEM; **p < 0.01, ***p < 0.001. f-h After suppression of transgene expression for 12 wks, aged rNLS8 mice show the same level of re-innervation of TA and Sol muscles compared to young rNLS8 mice. f-g. Representative muscle cryosections from the TA of a young (f) and aged (g) rNLS8 mouse after long transgene suppression. Scale bars = 100 μm. h Quantification of intact NMJs in young (red) and aged (blue) TA and Sol after recovery, n = 3–4, mean ± SD. i-j Evoked CMAPs in the GC muscle after stimulation of the sciatic nerve in young (red) and aged (blue) rNLS8 mice that are back on Dox after 6 wks off show a more robust motor recovery in young animals. i Individual traces from the same animals at two different time-points showing the M-wave. j CMAP measurements significantly decrease with hTDP-43 expression, but can recover following transgene suppression and muscle re- innervation. Unlike young rNLS8 mice, the aged mice never return to their original, pre-disease baseline and have significantly lower maximum evoked CMAPs from the GC than young rNLS8 mice after 8 and 10 week of recovery. Data are mean ± SD, n = 3–7 animals per genotype, *p < 0.05, **p < 0.01