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 4

hHsp27 overexpression accelerates axonal growth after nerve crush in vivo.

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hHsp27 overexpression accelerates axonal growth after nerve crush in viv...
(A) Gap-43 immunoreactivity was used to determine the extent of axonal regeneration 72 hours after a sciatic nerve crush injury in WT LMs and hHsp27 Tg mice 4.5 mm from the crush site (indicated by *). Scale bar: 100 μm. Schema of representative LM and Tg sciatic nerves, showing results of (B) Gap-43 immunoreactivity and (C) pinch test. Gap-43 fibers were quantified between 4.5 to 5 mm from the crush site. (B) hHsp27 Tg mice had more Gap-43 immunoreactive fibers per section compared with LMs (n = 3–5 per group; *P < 0.001, Student’s t test). (C) Sensory fiber regeneration, determined by the pinch test was significantly enhanced in hHsp27 Tg mouse lines that express hHsp27 in DRGs compared with that in LM controls (n = 10–12 per group; *P < 0.05, Student’s t test). (D) An intraneural injection of a peptide MK2 inhibitor (MK2i) (10 μM) was made distal to a sciatic nerve crush site in hHsp27 Tg mice, and the pinch test was performed 32 hours later. Axonal regeneration was decreased significantly in the MK2 inhibitor–treated groups (n = 6 per group; **P < 0.001, Student’s t test).