Accelerating axonal growth promotes motor recovery after peripheral nerve injury in mice
Chi Him Eddie Ma, Takao Omura, Enrique J. Cobos, Alban Latrémolière, Nader Ghasemlou, Gary J. Brenner, Ed van Veen, Lee Barrett, Tomokazu Sawada, Fuying Gao, Giovanni Coppola, Frank Gertler, Michael Costigan, Dan Geschwind, Clifford J. Woolf
Chi Him Eddie Ma, Takao Omura, Enrique J. Cobos, Alban Latrémolière, Nader Ghasemlou, Gary J. Brenner, Ed van Veen, Lee Barrett, Tomokazu Sawada, Fuying Gao, Giovanni Coppola, Frank Gertler, Michael Costigan, Dan Geschwind, Clifford J. Woolf
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Research Article

Accelerating axonal growth promotes motor recovery after peripheral nerve injury in mice

Abstract

Although peripheral nerves can regenerate after injury, proximal nerve injury in humans results in minimal restoration of motor function. One possible explanation for this is that injury-induced axonal growth is too slow. Heat shock protein 27 (Hsp27) is a regeneration-associated protein that accelerates axonal growth in vitro. Here, we have shown that it can also do this in mice after peripheral nerve injury. While rapid motor and sensory recovery occurred in mice after a sciatic nerve crush injury, there was little return of motor function after sciatic nerve transection, because of the delay in motor axons reaching their target. This was not due to a failure of axonal growth, because injured motor axons eventually fully re-extended into muscles and sensory function returned; rather, it resulted from a lack of motor end plate reinnervation. Tg mice expressing high levels of Hsp27 demonstrated enhanced restoration of motor function after nerve transection/resuture by enabling motor synapse reinnervation, but only within 5 weeks of injury. In humans with peripheral nerve injuries, shorter wait times to decompression surgery led to improved functional recovery, and, while a return of sensation occurred in all patients, motor recovery was limited. Thus, absence of motor recovery after nerve damage may result from a failure of synapse reformation after prolonged denervation rather than a failure of axonal growth.

Authors

Chi Him Eddie Ma, Takao Omura, Enrique J. Cobos, Alban Latrémolière, Nader Ghasemlou, Gary J. Brenner, Ed van Veen, Lee Barrett, Tomokazu Sawada, Fuying Gao, Giovanni Coppola, Frank Gertler, Michael Costigan, Dan Geschwind, Clifford J. Woolf

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Figure 8

Timing is crucial for functional motor recovery in mice and humans after nerve injury.

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Timing is crucial for functional motor recovery in mice and humans after...
(A) Cumulative percentage of animals (WT and Tg) with functional recovery after SNT/resuture. Functional recovery was defined as the first day the mice exhibited a positive response in pinprick (sensory response, n = 14–21 per group from 2 sensory lines) or toe spreading tests (motor response, n = 13–26 per group from 2 motor lines). (B) When the sciatic nerve was crushed 4 times with a 2-day interval (16 days of denervation), mice showed a full recovery in the toe spreading reflex. In contrast, when the crushes were performed 4 times with a 9-day interval (37 days of denervation), recovery was markedly reduced (n = 9 per group; *P < 0.0001, 1-way ANOVA with post-hoc Newman-Keuls test). (C) Sensory recovery in patients with CuTS. White circles represent the preoperative, and black represent the postoperative, mechanical threshold on the distal phalanx of the little finger. The dash lines represent the border between loss of protective sensation (I), diminished protective sensation (II), and diminished light touch (III) (n = 20; *P = 0.0012, Student’s t test). (D) Relationship between duration of symptoms and motor recovery in patients with CuTS. A value of 5 on the y axis represents normal muscle strength, and a value of 0 on the y axis represents complete denervation (n = 20; *P = 0.000029, Student’s t test). (E) Comparison of duration from onset to surgery in patients operated with complete target muscle denervation in CuTS (n = 20) and CTS (n = 136) (*P < 0.05; **P < 0.0001, Student’s t test).