Muscle atrophy and regeneration associated with behavioural loss and recovery of function after sciatic nerve crush.

Aim: To resolve timing and coordination of denervation atrophy and the re-innervation recovery process to discern correlations indicative of common programs governing these processes.

Methods: Female Sprague-Dawley (SD) rats had a unilateral sciatic nerve crush. Based on longitudinal behavioural observations, the triceps surae muscle was analysed at different time points post-lesion.

Results: Crush results in a loss of muscle function and mass (-30%) followed by a recovery to almost pre-lesion status at 30 days post-crush (dpc). There was no loss of fibres nor any significant change in the number of nuclei per fibre but a shift in fibres expressing myosins I and II that reverted back to control levels at 30 dpc. A residual was the persistence of hybrid fibres. Early on a CHNR -ε to -γ switch and a re-expression of embryonic MyHC showed as signs of denervation. Foxo1, Smad3, Fbxo32 and Trim63 transcripts were upregulated but not Myostatin, InhibinA and ActivinR2B. Combined this suggests that the mechanism instigating atrophy provides a selectivity of pathway(s) activated. The myogenic differentiation factors (MDFs: Myog, Myod1 and Myf6) were upregulated early on suggesting a role also in the initial atrophy. The regulation of these transcripts returned towards baseline at 30 dpc. The examined genes showed a strong baseline covariance in transcript levels which dissolved in the response to crush driven mainly by the MDFs. At 30 dpc the naïve expression pattern was re-established.

Conclusion: Peripheral nerve crush offers an excellent model to assess and interfere with muscle adaptions to denervation and re-innervation.